Gerd Blobel, M.D., Ph.D.

1) We are pursuing questions of how chromatin in organized in the nucleus, specifically, how enhancer-promoter contacts are formed or constrained. We found that the hematopoietic transcription factor GATA1 and its co-factor FOG1 are essential to juxtapose the enhancer of the b-globin locus with the promoter (Vakoc, Mol. Cell 2005). This study was among the first to define any nuclear factor in chromatin looping. We discovered that chromatin looping is highly dynamic and can occur even at repressed genes (Jing, Mol. Cell 2008). Using a novel approach of tethering the “looping” factor Ldb1 to an endogenous gene, we were able for the first time to generate an enhancer-promoter chromatin loop at a native endogenous gene locus and thus discovered that chromatin looping causally underlies gene expression (Deng et al., Cell 2012). We adapted this approach to reprogram the murine and human b-globin to reactivate the dormant embryonic and fetal globin genes, respectively (Deng, Cell 2014). We are advancing this strategy towards a clinical application in the setting of sickle cell anemia and thalassemia.

We discovered a novel developmental stage specific chromatin architectural element that constrains the functional range of the b-globin enhancer (Huang, Genes Dev. 2017). This element is a potential target for therapeutic genome editing.

By examining the chromosomal architecture during transcription elongation in erythroid cells we discovered that at some genes, instead of the RNA polymerase tracking down the gene, the gene is reeled alongside a polymerase complex that is stabilized by enhancer promoter loops (Lee et al., Genes Dev. 2015). This discovery modifies long-standing views of how transcription progresses in the nucleus.

  • Deng W, Lee J, Wang H, Reik A, Gregory PD, Dean A, and Blobel GA(2012) Controlling long-range chromosomal interactions at a native locus by targeted tethering of a looping factor. Cell149:1233-44. (Featured in a Cell video, and selected by Faculty of 1000) [PMCID: PMC3600827]
  • Deng W, Rupon JW, Krivega, I, Breda L, Motta, I, Jahn KS, Reik A, Gregory PD, Rivella S, Dean A, Blobel GA(2014) Reactivation of developmentally silenced globin gene expression by forced chromatin looping. Cell, 158:849-60. Selected by Faculty of 1000, and highlighted in Nature Genetics [PMCID: PMC4134511]
  • Lee K, Hsiung CC-S, Huang P, Raj A and Blobel GA(2015) Dynamic enhancer-gene body contacts during transcription elongation. Genes Dev., 29:1992-1997.
  • Huang P, Keller CA, Giardine B, Grevet, JD, Davies JOJ, Hughes JR, Kurita R, Nakamura Y, Hardison RC, and Blobel GA(2017) Comparative analysis of 3-dimensional chromosomal architecture identifies novel fetal hemoglobin regulatory element. Genes Dev. 31:1704-1713. [PMCID: PMC5647940]

2) A key question in the establishment and maintenance of cellular lineages is how transcriptional programs are stably maintained throughout the cell cycle to preserve lineage identity. This question is intimately related to how transcription factors interact with the appropriate gene-specific elements within chromatin and how these interactions are controlled throughout the cell division cycle. During mitosis chromosomes condense and transcription is silenced globally as a result of eviction of most nuclear factors from chromatin. Our studies have been aimed at understanding how the cell epigenetically “remembers” to restore appropriate transcription patterns upon G1 entry. By studying the tri-thorax protein MLL and the hematopoietic transcription factor GATA1 we have gained important insights into mitotic “bookmarking” mechanisms, including the first genome wide location analyses of transcription factors in pure mitotic populations (Blobel, Mol. Cell. 2009; Kadauke, Cell 2012) and functional insights into post-mitotic reactivation of bookmarked vs non-bookmarked genes. In the process we developed key reagents that are being used by many others in the field, including a new method to purify mitotic cells to virtual homogeneity and new tools to degrade proteins of interest specifically in mitosis. We have carried out the first genome wide survey of chromatin accessibility in pure mitotic chromatin and found that remarkably, that chromosome retain most of their “openness” with enhancers being more susceptible to partial loss of accessibility that promoters (Hsiung, Genome Res. 2015). We have examined for the first time on a global scale how the genome is transcriptionally reawakened following mitosis and discovered a window in time at which the genome is hyperactive and at which cell to cell variation in transcription patterns is established (Hsiung, Genes Dev. 2016). We also describe how genome architecture is hierarchically re-built when cells exit mitosis and re-enter the G-1 phase of the cell cycle. (Zhang, Nature, 2019)

  • Blobel GA, Kadauke S, Wang E, Lau AW, Zuber J, Chou MM, and Vakoc CR (2009). A Reconfigured Pattern of MLL Occupancy within Mitotic Chromatin Promotes Rapid Transcriptional Reactivation Following Mitotic Exit. Molecular Cell, 36:970-983. [PMCID: PMC2818742] (Preview in Developmental Cell 18:4, 2010).
  • Kadauke S, Udugama M., Pawlicki JM, Achtman JC, Jain DP, Cheng Y, Hardison RC, and Blobel GA(2012) Tissue-specific Mitotic Bookmarking by Hematopoietic Transcription Factor GATA1. Cell 150:725-737. [PMCID: PMC3425057]
  • Hsiung CC-S, Morrissey C, Udugama M, Frank CL, Keller CA, Baek S, Giardine B, Crawford GE, Sung M-H, Hardison RC, Blobel GA(2015) Genome accessibility is widely preserved and locally modulated during mitosis. Genome Research, 2:213-25 [PMCID: PMC4315295]
  • Hsiung CC-S, Bartman C, Huang P, Ginart P, Stonestrom AJ, Keller CA, Face C, Jahn KS, Evans JP, Sankaranarayanan L, Giardine B, Hardison RC, Raj A, Blobel GA(2016) A hyperactive transcriptional state marks genome reactivation upon mitotic exit. Genes Dev. 30:1423-39. [PMCID: PMC 4926865]

3) We are interested in the factors that establish higher order chromatin organization and how long range chromatin interactions impact on transcription. We used forced chromatin looping in combination with single molecule RNA-FISH to understand mechanistically how enhancer-promoter contacts impact on transcription output and to define the dynamics of chromatin looping (Bartman, Mol. Cell 2016, Bartman, Mol. Cell 2019).

We examine how architectural factors such CTCF and cohesins function in organizing the genome and how the impact enhancer promoter communication and gene expression. We discovered that the epigenetic “reader” BET protein BRD2 and the architectural transcription factor CTCF and found that BRD2 contributes to the formation of chromatin boundaries that insulate enhancers from contacting and activating inappropriate genes (Hsu, Molecular Cell 2017). We profiled CTCF and cohesin during the cell cycle and linked these molecules to hierarchical genome folding when cells exit mitosis and enter the G1 phase of the cell cycle (Zhang, Nature 2019). We are examine chromatin contacts and domain boundaries via gain-of-function perturbative studies (Zhang, Nature Genetics 2020).

  • Bartman CR, Hsiung CC-S, Raj A, Blobel GA(2016) Enhancer regulation of transcriptional bursting parameters revealed by forced chromatin looping. Molecular Cell 62:237-247 [PMCID: PMC4842148]
  • Hsu SC, Bartman CR, Gilgenast TG, Edwards, CR, Stonestrom AJ, Huang P, Emerson DJ, Evans P, Werner MT, Keller CA, Giardine ., Hardison RC, Raj A, Phillips-Cremins JE and Blobel GA (2017) The BET protein BRD2 cooperates with CTCF to enforce architectural and transcriptional boundaries. Molecular Cell  66:102-116 (Selected by Faculty of 1000) [PMCID: PMC5393350]
  • Zhang H, Emerson DJ, Gilgenast TG, Titus KR, Lan Y, Huang P, Zhang D, Wang H, Keller CA, Giardine B. Hardison RC, Phillips-Cremins JE, and Blobel GA(2019) Chromatin Structure Dynamics During the Mitosis to G1-Phase Transition. Nature, 576:158-162 [PMCID: PMC6895436]
  • Zhang D, Huang P, Keller CA, Giardine B, Zhang H, Gilgenast TG, Phillips-Cremins JE, Hardison RC, and Blobel GA(2020) Alteration of genome folding via engineered boundary insertion. Nature Genetics, 52:1076-1087 (featured in News and Views) [PMCID: PMC7541666]

4) We are aim to find new modalities to raise fetal hemoglobin production to benefit patients with sickle cell disease and thalassemia. Recently our focus has been to identify molecules involved in fetal hemoglobin regulation that might be druggable. We improved CRISPR-Cas9 technology as a screening tool and employed it to discover an erythroid specific protein kinase HRI as regulator of fetal hemoglobin (Grevet, Science 2018). We followed up with mechanistic studies elucidating the pathway leading from HRI to fetal globin silencing (Huang et al. 2020). Using this CRISPR screening approach we discovered a new zinc finger transcription factor, ZNF410, that is potentially targetable via a PROTAC that silences fetal hemoglobin transcription via a single target gene, the NuRD subunit CHD4 (Lan, Molecular Cell, 2020). Deep mechanistic studies include the clinically relevant question as to why some cells respond to fetal hemoglobin induction while others do not (Khandros, Blood 2020).

  • Grevet JD, Lan X, Hamagami N, Edwards CR, Sankaranarayanan L, Ji X, Bhardwaj SK, Face CJ, Posocco DF, Abdulmalik O, Keller CA, Giardine B, Sidoli S, Garcia BA, Chou ST, Liebhaber SA, Hardison RC, Shi J, and Blobel GA(2018) Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells. Science 361:285-290 (Preview in the New England Journal of Medicine 379:17,2018) [PMCID:PMC6257981]
  • Huang P, Peslak SA, Lan X, Khandros E, Yano JA, Sharma M, Keller CA, Giardine B, Qin K, Abdulmalik O, Hardison RC, Shi J  and Blobel GA(2020). HRI activates ATF4 to promote BCL11A transcription and fetal hemoglobin silencing. Blood, 135:2121-2132 (Plenary paper, featured in Preview) [PMCID: PMC7290097]
  • Lan X. Ren R., Feng R., Ly L.C., Lan Y., Zhang Z., Aboreden N., Qin K., Horton J.R., Grevet J.D.,Mayuranathan T.,Abdulmalik O., Keller C.A., Giardine B., Hardison R.C., Crossley M., Weiss M.J., Cheng X., Shi J., Blobel G.A. (2020) ZNF410 uniquely activates the NuRD component CHD4 to silence fetal hemoglobin expression. Molecular Cell, in press
  • Khandros E., Huang P., Peslak S.A., Sharma, M., Abdulmalik O., Giardine B., Zhang Z., Keller C.A., Hardison R.C., and Blobel G.A. (2020). Understanding Heterogeneity of Fetal Hemoglobin Induction through Comparative Analysis of F- and A-erythroblasts. Blood135;1957-1968 (featured in Preview) [PMCID: PMC7256358]

 

Complete List of Published Work in MyBibliography 

https://www.ncbi.nlm.nih.gov/myncbi/1-Q-j5i56qQAo/bibliography/public/

Research Interest

We study how genetic regulatory elements are organized spatially in the nucleus and how transcription programs and chromatin architecture are organized throughout the cell cycle to maintain lineage identity. A major effort in the lab is directed towards understanding the regulation of globin gene expression and developing approaches to perturb globin gene expression to ameliorate sickle cell disease. Our work bridges basic science with preclinical studies. For our studies we combine molecular, genomic, biochemical, and imaging approaches with studies in normal and gene targeted mice.

Maya Capelson, Ph.D.

Contact Information

The Perelman School of Medicine at the University of Pennsylvania
Department of Cell and Developmental Biology
9-101 Smilow Center for Translational Research
3400 Civic Center Blvd
Philadelphia, PA 19104-6059
Office: 215-898-0550
Lab: 215-573-7548
capelson@pennmedicine.upenn.edu

Robert Babak Faryabi, Ph.D.

Deciphering Mechanisms of Genome Mis-folding In Cancer

Our lab deploys data-rich experimental techniques to elucidate the role of genome mis-folding in controlling oncogenic gene expression programs. Specifically, we are interested in moving beyond the status quo to understand how oncogenic subversion of lineage-determining transcription factors set topology of cancer genome. To tackle this question, we combine genomics and super-resolution imaging and focus on investigating molecular mechanisms of genome mis-folding in breast and blood cancers. These mechanistic studies aim to identify precise epigenetic vulnerabilities of cancer cells and guide treatments disrupting cancer cells’ transcriptional addiction.

Representative Publication:

Oncogenic Notch Promotes Long-Range Regulatory Interactions Within Hyperconnected 3D Cliques. Petrovic J*, Zhou Y*, Fasolino M, Goldman N, Schwartz GW, Mumbach MR, Nguyen SC, Rome KS, Sela Y, Zapataro Z, Blacklow SC, Kruhlak MJ, Shi J, Aster JC, Joyce EF, Little SC, Vahedi G, Pear WS, Faryabi RB Molecular Cell. 2019;73(6):1174-90 e12

Determining Epigenetic Mechanisms Of Resistance To Targeted Therapies

Targeting oncogenic drivers of cancers commonly leads to drug resistance. Mechanisms of acquiring resistance to oncology drugs mostly remain unknown, partly due to the limitations of population-based assays in elucidating heterogeneity of drug-naive and complexity of drug-induced tumor evolution. Using single-cell genomics and imaging, we study how heterogeneity and plasticity of transcriptional dependencies confer resistance to targeted therapeutics such as Notch inhibitors.

Representative Publication

TooManyCells Identifies And Visualizes Relationships Of Single-cell Clades. Schwartz GW, Zhou Y, Petrovic J, Fasolino M, Xu L, Shaffer SM, Pear WS, Vahedi G, Faryabi RB Nature Methods, 2020; 17: 405-413

Innovating Computational Methods To Enable Cancer Discovery

Our lab innovates statistical and machine learning approaches to accelerate discovery of novel therapeutics and biomarkers by elucidating complexity and heterogeneity of tumors. Recently, we have developed a computational ecosystem for mapping molecular and spatial heterogeneity in tumors. As part of the Center for Personalized Diagnostics, we also mine cancer patient genotypic/phenotypic data to improve patient health. patient health.

Representative Publication:

Classes of ITD Predict Outcomes in AML Patients Treated With FLT3 Inhibitors. Schwartz GW, Manning B, Zhou Y, Velu P, Bigdeli A, Astles R, Lehman AW, Morrissette JJD, Perl AE, Li M, Carroll M, Faryabi RB Clinical Cancer Research. 2019;25(2):573-83

Research Interest

Cancer is typically considered a genetic disease. However, recent progress in our understanding of epigenetic aberrations in cancer has challenged this view. Overarching goal of our lab is to understand epigenetic mechanisms of transcriptional addiction in cancer and exploit this information to advance cancer therapeutics.

To pursue this objective, we use cutting-edge chromatin conformation capture, high-content imaging, single-cell epigenomics, functional genomics, and combine these technologies with our expertise in computational sciences to systematically explore: i) how epigenetic control of gene expression is disrupted in cancer, ii) why transcriptional addiction can develop, and iii) how heterogeneity and plasticity of transcriptional dependencies enable drug resistance.

Kathryn E. Wellen, Ph.D.

1. Role of STAMP2 (STEAP4) in modulating inflammatory and metabolic responses in adipocytes: My interest in metabolism began while I was a graduate student in the laboratory of Gökhan S. Hotamisligil. My work in the Hotamisligil lab specifically focused on the role of six-transmembrane protein of prostate 2 (STAMP2; also known at STEAP4). We because interested in STAMP2 from a gene expression study that I performed at the start of my graduate training, in which we found that STAMP2 expression was induced by the inflammatory cytokine TNFα and suppressed by thiazolidinediones (Endocrinology, 2004). During the rest of my graduate training years, I worked to elucidate the function of STAMP2 in adipocytes, using both cell culture and mouse models. We found that STAMP2 acts to prevent inappropriate activation of inflammatory pathways in adipocytes, thereby contributing to the maintenance of systemic insulin sensitivity (Cell, 2007). We also published an influential review article that has been cited over 4000 times to date.
Wellen KE, Uysal KT, Wiesbrock S, Yang Q, Chen H, Hotamisligil GS. Interaction of tumor necrosis factor-alpha- and thiazolidinedione-regulated pathways in obesity. Endocrinology. 2004 May;145(5):2214-20. PubMed PMID: 14764635.
Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005 May;115(5):1111-9. PubMed PMID: 15864338; PubMed Central PMCID: PMC1087185.
Wellen KE, Fucho R, Gregor MF, Furuhashi M, Morgan C, Lindstad T, Vaillancourt E, Gorgun CZ, Saatcioglu F, Hotamisligil GS. Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell. 2007 May 4;129(3):537-48. PubMed PMID: 17482547; PubMed Central PMCID: PMC2408881.
The hexosamine biosynthetic pathway in coordination of metabolic and signaling pathways: After obtaining my PhD, I joined Craig B. Thompson’s laboratory, to further develop my expertise in cellular metabolism and gain training in the re-emerging field of cancer metabolism. I sought to understand how cells gauge nutrient availability and, to this end, investigated the role of the hexosamine biosynthetic pathway, which generates the glycosyl donor UDP-GlcNAc. We found that glucose utilization in the hexosamine pathway impacts growth factor receptor N-glycosylation and surface presentation, and that this serves as a mechanism to coordinate glucose and glutamine metabolism to support proliferation in hematopoietic cells (Genes and Development, 2010). More recently, we have reexamined the regulation of the hexosamine pathway under conditions of nutrient deprivation, identifying that pancreatic cancer cells employ a little studied hexosamine salvage pathway in response to glutamine deprivation to feed UDP-GlcNAc pools (eLife, 2021).
Wellen KE, Lu C, Mancuso A, Lemons JM, Ryczko M, Dennis JW, Rabinowitz JD, Coller HA, Thompson CB. The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism. Genes Dev. 2010 Dec 15;24(24):2784-99. PubMed PMID: 21106670; PubMed Central PMCID: PMC3003197.
Wellen KE, Thompson CB. A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol. 2012 Mar 7;13(4):270-6. PubMed PMID: 22395772.
Campbell SL and Wellen KE. Metabolic Signaling to the Nucleus in Cancer. Mol Cell, 2018 Aug 2; 71(3): 398-408. PMID: 30075141.
Campbell SL, Mesaros C, Izzo L, Affronti H, Noji M, Schaffer, BE, Tsang T,  Sun K,  Trefely S, Kruijning S, Blenis J, Blair IA, Wellen KE. Glutamine deprivation triggers NAGK-dependent hexosamine salvage, eLife, 2021
Acetyl-CoA at the interface of lipid metabolism and epigenetics: roles in cellular and organismal physiology: My interest in metabolic regulation of the epigenome, which constitutes a major current focus on my lab, also developed during my postdoctoral work in the Thompson lab. When I joined the Thompson lab in 2006, the lab had been studying acetyl-CoA metabolism and its role in supporting tumor growth through de novo lipid synthesis. Whether acetyl-CoA levels are also regulatory for lysine acetylation had been speculated and evidence for this had emerged in yeast, but little to no evidence for this possibly existed in mammalian cells. We found that acetyl-CoA production by ATP-citrate lyase (ACLY) is critical for maintaining overall levels of histone acetylation in multiple mammalian cell types, including adipocytes. This initial study, published in Science, was one of the first papers demonstrating metabolic control of the epigenome in mammalian cells. Since starting my own laboratory in 2011, we have extensively investigated the role of acetyl-CoA metabolism in regulation of lipid metabolism and the epigenome. We reported the development of Aclyf/f mice and MEF cell lines, as well as Adiponectin-Cre;Aclyf/f (adipocyte-specific KO) mice (Cell Reports, 2016). Using these reagents, we demonstrate that upregulation of ACSS2 and engagement of acetate metabolism is a key mechanism of compensation to supply acetyl-CoA for histone acetylation and lipid synthesis in the absence of ACLY, in vitro and in vivo. We further found that fructose metabolism to acetate produced by gut microbiota represents a key source of acetyl-CoA for hepatic lipogenesis (Nature, 2020). We also demonstrated that ACLY is crucial for sucrose-induced activation of ChREBP in adipocytes and in sustaining systemic metabolic homeostasis during carbohydrate feeding (Cell Reports, 2019).
Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science. 2009 May 22;324(5930):1076-80. PubMed PMID: 19461003; PubMed Central PMCID: PMC2746744.
Zhao S, Torres AM, Henry R, Trefely T, Wallace M, Lee JV, Carrer A, Sengupta A, Kuo YM, Frey AJ, Meurs N, Viola JM, Blair IA, Weljie A, Snyder NW, Andrews AJ, Wellen KE. ATP-citrate lyase controls a glucose-to-acetate metabolic switch, Cell Rep, 2016, Oct 18;17(4):1037-1052. Pubmed PMID: 27760311; PubMed Central PMCID: PMC5175409
Fernandez S, Viola JM, Torres A, Wallace M, Trefely S, Zhao S, Affronti HC, Gengatharan JM, Guertin DA, Snyder NW, Metallo CM, Wellen KE. Adipocyte ACLY facilitates dietary carbohydrate handling to maintain metabolic homeostasis in females. Cell Rep, 2019, May 28;27(9):2772-2784. PubMed PMID:31141698; PubMed Central PMCID: PMC6608748
Zhao S, Jang C, Liu J, Uehara K, Gilbert M, Izzo L, Zeng X, Trefely S, Fernandez S, Carrer A, Miller KD, Schug ZT, Snyder NW, Gade TP, Titchenell PM, Rabinowitz JD, Wellen KE. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate, Nature. 2020, Mar;579(7800):586-591. PubMed PMID: 32214246.
Acetyl-CoA at the interface of lipid metabolism and epigenetics: roles in tumor development and progression. A major emphasis of my laboratory has been to investigate the role of acetyl-CoA metabolism and metabolic control of the epigenome in tumor development and progression. One of the key questions we have sought to answer is whether oncogene-mediated metabolic rewiring impacts acetyl-CoA pools in such a way as to modulate the tumor epigenome. We found that oncogenic activation of the PI3K-AKT pathway promotes nuclear-cytosolic acetyl-CoA production and histone acetylation via ATP-citrate lyase (ACLY). Consistently, in human tumors, we identified a significant positive correlation between pAKT-S473 and histone acetylation levels. This study was published in Cell Metabolism and was one of the first demonstrations that oncogenic metabolic reprogramming contributes to alterations in the tumor epigenome independent of mutations in genes encoding metabolic enzymes. Following up on this study, we have identified a role for ACLY-S455 phosphorylation within the nucleus in providing acetyl-CoA for histone acetylation near sites of DNA double strand breaks, which facilitates BRCA1 recruitment and DNA repair by homologous recombination (Molecular Cell, 2017). We have also found that ACLY is crucial for KRASG12D-driven histone acetylation in pancreatic acinar cells and plays a distinct role in supporting acinar-to-ductal metaplasia in early pancreatic tumorigenesis. Once tumors form, however, ACSS2 is highly expressed and tumors can grow even in the absence of ACLY. Despite this metabolic flexibility, we found that targeting of downstream acetyl-CoA producing processes, specifically the mevalonate pathway and the reading of acetyl-lysine, can suppress tumor growth (Cancer Discovery, 2019). Most recently, in collaborative work with Nathaniel Snyder, we have developed methodology for compartmentalized acyl-CoA analysis termed SILEC-SF and leveraged this approach to discover that propionyl-CoA is enriched in the nucleus and that isoleucine catabolism feeds nuclear propionyl-CoA pools and histone lysine propionylation (Trefely et al, Mol Cell, 2022).

Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, Worth AJ, Yuan ZF, Lim HW, Liu S, Jackson E, Aiello NM, Haas NB, Rebbeck TR, Judkins A, Won KJ, Chodosh LA, Garcia BA, Stanger BZ, Feldman MD, Blair IA, Wellen KE. Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab. 2014 Aug 5;20(2):306-19. PubMed PMID: 24998913; PubMed Central PMCID: PMC4151270.
Sivanand S, Rhoades S, Jiang Q, Viney I, Zhang J, Tang J, Benci J, Yuan S, Zhao S, Carrer A, Bennett MJ, Minn AJ, Weljie AM, Greenberg RA, Wellen KE. Nuclear acetyl-CoA production by ACLY promotes homologous recombination, Mol Cell, 2017 Jul 20 Jul 20;67(2):252-265. PubMed PMID: 28689661; PubMed Central PMCID: PMC5580398
Carrer A, Trefely S, Zhao S, Campbell SL, Norgard RJ, Schultz KC, Sidoli S, Parris JLD, Affronti HC, Sivanand S, Egolf S, Sela Y, Trizzino M, Gardini A, Garcia BA, Snyder NW, Stanger BZ, Wellen KE. Acetyl-CoA metabolism supports multi-step pancreatic tumorigenesis. Cancer Discov. 2019 Mar;9(3):416-435. PubMed PMID: 30626590; PubMed Central PMCID: PMC6608748
Trefely S, Huber K, Liu J, Noji M, Stransky S, Singh J,  Doan MT, Lovell CD, von Krusenstiern E, Jiang H, Bostwick A, Pepper HL, Izzo L, Zhao Z, Xu JP, Bedi Jr KC, Rame JE,  Sidoli S, Bogner-Strauss J, Mesaros C, Wellen KE*, Snyder NW*. Quantitative sub-cellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation, Mol Cell, 2022 (*co-corresponding authors)

Research Interest

cancer metabolism, metabolic regulation of the epigenome, metabolic signaling

Hongjun Song, Ph.D.

Mechanisms regulating adult hippocampal neural stem cells and neurogenesis.
Adult hippocampal neurogenesis reflects a remarkable form of structural plasticity in the mature mammalian brain. Fully characterizing this phenomenon could have far-reaching implications for understanding hippocampal function and revealing fundamental properties of neural development and the regenerative capacity of the central nervous system. Over the past 14 years, my laboratory has systemically investigated adult hippocampal neurogenesis at the molecular, cellular, and circuit levels and reported a number of key findings that have influenced the field. Via genetic clonal analysis, we conclusively demonstrated, for the first time, the existence of bona fide neural stem cells in the adult mammalian hippocampus, capable of both self-renewal and multipotent fate specification of progeny (Bonaguidi et al., Cell 2011). We also revealed how neural activity and experience can regulate the behavior of these stem cells (Song et al., Nature 2012; Jang et al. Cell Stem Cell 2013). We provided the first detailed characterization of newborn neuron integration into the existing neuronal circuitry and its underlying molecular, cellular and circuitry mechanisms (Ge et al., Nature 2006; Faulkner et al. PNAS 2009; Kang et al. Neuron 2011; Kim et al. Cell 2012; Sun et al. J Neurosci. 2013; Song et al. Nat. Neurosci. 2013). In collaboration with Dr. Guo-li Ming, we have discovered critical roles of DISC1, a psychiatric disorder risk gene, in regulating the development of newborn neurons during adult hippocampal neurogenesis (Duan et al. Cell 2007; Faulkner et al. PNAS 2008, Kim et al Neuron 2009; Kim et al. Cell 2012; Zhou et al. Neuron 2013). We discovered novel circuitry mechanisms whereby local neural activity influences the proliferation and development of newborn neurons in the hippocampus (Ma et al., Science 2009; Song et al., Nature 2012; Song et al., Nat Neurosci 2013).

Duan, X., Chang, J.H., Ge, S-y., Faulkner, R.L., Kim, J.Y., Kitabatake, Y., Liu, X-b., Yang, C-h., Jordan, J.D., Ma, D.K., Liu, C.Y., Ganesan, S., Cheng, H.J., Ming, G-l.*, Lu, B.* and Song, H-j.* (2007). Disrupted-In-Schizophrenia 1 regulates integration of new neurons in the adult brain. Cell 130, 1146-1158.
Bonaguidi, M.A., Wheeler, M., Shapiro, J.S., Stadel, R., Sun, G.J., Ming, G-l.*, and Song, H*. (2011). In vivo clonal analysis reveals self-renew and multipotent adult neural stem cell characteristics. Cell 145, 1142-55.
Song, J., Zhong, C., Bonaguidi, M.A., Sun, G.J., Hsu1, D., Gu, Y., Meletis, K., Huang, Z.J., Ge, S., Enikolopov, G., Deisseroth, K., Luscher, B., Christian, K., Ming, G-l., and Song, H. (2012). Neuronal circuitry mechanism regulating adult quiescent neural stem cell fate decision. Nature 489, 150-4.
Sun, G.J., Zhou, Y., Ito, S., Bonaguidi, M.A., Stein-O’Brien, G., Kawasaki, N., Modak, N., Zhu, Y., Ming, G-l., and Song, H. (2015). Latent tri-lineage potential of adult neural stem cells in the hippocampus revealed by Nf1 inactivation. Nature Neuroscience 18, 1722-4.

Neuroepigenetics and Neuroepitranscriptomics. Contrary to the long-held dogma that DNA methylation is a stable epigenetic mark in post-mitotic neurons, it is now recognized to be a robust form of plasticity in the adult nervous system. We have made significant contributions to the current understanding of epigenetic DNA modifications in the adult nervous system. My laboratory identified the first molecular mechanism regulating active DNA demethylation in mature neurons in vivo (Ma et al. Science 2009) and subsequently delineated molecular pathways mediating this process (Guo et al. Cell 2011). More recently, we showed that the neuronal DNA demethylation pathway plays fundamental roles in neuronal function, including regulation of basal levels of synaptic transmission and homeostatic synaptic plasticity (Yu et al. Nat. Neurosci. 2015). My laboratory has established a pipeline for high-throughput sequencing analysis, including RNA-seq, Chip-seq, Bisulfite-seq, ATAC-seq and single-cell RNA-seq and we have designed custom software programs for bioinformatic analyses. We published the first single-base resolution genome-wide DNA methylation profiles in neurons in vivo and showed large scale neuronal activity-induced dynamic methylation changes (Guo et al. Nat. Neurosci, 2011). Via single-base methylome analysis, we also demonstrated the presence of prominent nonCpG methylation in mature neurons in vivo and identified MeCP2 as the first nonCpG DNA methylation binding protein in the field (Guo et al. Nat. Neurosci. 2014). More recently, we have started to explore how methylation of mRNA can affect neurogenesis, axon regeneration and plasticity (Yoon et al. Cell 2017; Weng et al. Neuron 2018).

Ma, D.K., Jang, M.H., Guo, J.U., Kitabatake, Y., Chang, M.L., Pow-Anpongkul, N., Flavell, R.A., Lu, B., Ming, G.L., and Song, H-j. (2009). Neuronal activity-induced Gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 323, 1074-7.
Guo, J.U., Su, Y., Zhong, C., Ming, G.L., and Song, H. (2011). Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145, 423-34.
Yu, H., Su, Y., Shin, J., Zhong, C., Guo, J.U., Weng, Y-l., Gao, F., Geschwind, D.H., Coppola, G., Ming, G-l., and Song, H. (2015). Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nature Neuroscience 18, 836-843.
Yoon, K.J., Ringeling, F.R., Vissers, C., Jacob, F., Pokrass, M., Jimenez-Cyrus, D., Su, Y., Kim, N.S., Zhu, Y., Zheng, L., Kim, S., Wang, X., Doré, L.C., Jin, P., Regot, S., Zhuang, X., Canzar, S., He, C., Ming, G.L., and Song, H. (2017). Temporal control of mammalian cortical neurogenesis by m6A methylation. Cell 171(4):877-889.

Single-cell biology. A complete understanding of the structure and function of neural systems will require integrated analyses at multiple levels. A daunting obstacles to reaching this goal is the technical challenge of characterizing the behavior of single cells in vivo. Many neural processes can be described at the population level, but there are several domains where it is critical to identify molecular and functional properties at the single cell level. My laboratory has developed a “single cell genetic” approach to manipulate target genes in newborn neurons using retroviruses that led to a number of critical discoveries (Ge et al. Nature 2006; Duan et al, Cell 2007; Kim et al. Neuron 2009; Kang et al. Neuron 2011; Kim et al. Cell 2011; Jang et al. Cell Stem Cell 2013; Song et al. Nat. Neurosci. 2013). Our identification of bona fide neural stem cells in the adult brain required clonal analysis to determine whether radial glial-like cells were capable of both self-renewal and giving rise to multiple cell types, thus settling a debate in the field over whether neurons and glia were generated from lineage-restricted progenitors, as opposed to true stem cells (Bonaguidi et al. Cell 2011). To visualize dendritic and axonal growth over development, we devised a new strategy to allow us to reconstruct complete cellular processes of individual cells, revealing a stereotyped pattern of axonal targeting that further suggests the existence of guidance cues in the adult hippocampus (Sun et al., J Neurosci 2013). We have recent developed a single-cell RNA-seq technology and a bioinformatics pipeline to investigate transcriptomes of hundreds to thousands of heterogeneous cell types (Shin et al. Cell Stem Cell, 2015).

Ge, S-y., Goh. E.L.K., Sailor, K.A., Kitabatake, Y., Ming, G-l*. and Song, H-j*. (2006). GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589-593.
Bonaguidi, M.A., Wheeler, M., Shapiro, J.S., Stadel, R., Sun, G.J., Ming, G-l.*, and Song, H*. (2011). In vivo clonal analysis reveals self-renew and multipotent adult neural stem cell characteristics. Cell 145, 1142-55.
Jang, M., Bonaguidi, M.A., Kitabatake, Y., Sun, J., Song, J., Kang, E., Jun, H., Zhong, C., Su, Y., Guo, J.U., Wang, M.X., Sailor, K.A., Kim, J.Y., Gao, Y., Christian, K.M., Ming, G-l., and Song, H. (2013). Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis. Cell Stem Cell 12, 215-23.
Shin, J., Berg, D.A., Zhu, Y., Shin, J.Y., Song, J., Bonaguidi, M.A., Enikolopov, G., Nauen, D.W., Christian, K.M., Ming, G-l., and Song, H. (2015). Single-cell RNA-seq with Waterfall reveals molecular cascades underlying adult neurogenesis. Cell Stem Cell 17, 360-72.

Research Interest

Research in Dr. Hongjun Song’s laboratory focuses on two core topics: (1) neural stem cell regulation and neurogenesis in the developing and adult mammalian brain and how these processes affect neural function; (2) epigenetic and epitranscriptomic mechanisms and their functions in the mammalian nervous system. The lab is also interested in addressing how dysfunction of these mechanisms may be involved in brain disorders.

Brian C. Capell, M.D., Ph.D.

  • Demonstrated the first role for ferroptosis in epidermal differentiation and tumor suppression: Our recent studies have uncovered a potential link between the emerging form of programmed cell death known as ferroptosis and the execution of both epidermal differentiation and tumor suppression in the skin. Beyond identifying the mechanisms through which MLL4 (KMT2D) promotes differentiation and exerts its tumor suppressive functions, these studies have revealed evidence that ferroptosis may be the essential mechanism by which keratinocytes ultimately die and form the cornified envelope of the epidermal barrier. Given that numerous skin disorders are driven by dysregulated epidermal differentiation, combined with the ability to both pharmacologically induce and inhibit ferroptosis, these studies have provided proof of principal that ferroptosis modulation may a viable therapeutic strategy for a variety of skin disorders.

a.    Egolf S, Zou J, Anderson A, Simpson CL, Aubert Y, Prouty S, Ge K, Seykora JT, Capell BC. MLL4 mediates differentiation and tumor suppression through ferroptosis. Sci Adv. 2021 Dec 10;7(50):eabj9141. doi: 10.1126/sciadv.abj9141. Epub 2021 Dec 10. PMID: 34890228; PMCID: PMC8664260.

Research Interest

The Capell Lab seeks to understand epigenetic gene regulatory mechanisms, how they interface with metabolism and the immune system, and how when disrupted, they may contribute to disease, and in particular, cancer. By combining the incredible accessibility of human skin with the most cutting-edge techniques, we aim to identify therapeutic vulnerabilities in cancer, and novel targets to treat disease.

Erica Korb, Ph.D

The role of chromatin in neurodevelopmental disorders and disease.

Epigenetic regulation plays a critical role in many neurodevelopmental disorders, including Autism Spectrum Disorder (ASD). In particular, many such disorders are the result of mutations in genes that encode chromatin modifying proteins. However, while these disorders share many features, it is unclear whether they also share gene expression disruptions resulting from the aberrant regulation of chromatin. We examined 5 chromatin modifiers that are all linked to ASD despite their different roles in regulating chromatin. Using RNA-sequencing, we identified a transcriptional signature that is shared between multiple neurodevelopmental syndromes, helping to elucidate the link between epigenetic regulation and the underlying cellular mechanisms that result in ASD.

During the COVID-19 shut-down, we sought to apply our understanding of histone biology to better understand the ability of SARS-CoV-2 to evade the immune system. In rare cases, viral proteins dampen antiviral responses by mimicking critical regions of human histone proteins particularly those containing posttranslational modifications required for transcriptional regulation. We found that the SARS-CoV-2 protein encoded by ORF8 (Orf8) functions as a histone mimic of the ARKS motifs in histone 3. Orf8 is associated with chromatin, binds to numerous histone-associated proteins, and is itself acetylated at this site. Orf8 expression disrupts multiple critical histone post-translational modifications including H3K9ac, H3K9me3, and H3K27me3 and promotes chromatin compaction while Orf8. Further, SARS-CoV-2 infection in human cells and patient lung tissue cause these same disruptions to chromatin acting through the Orf8 histone mimic motif. These findings define a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation.

In my postdoctoral work in the lab of Dr. C. David Allis, I studied Fragile X syndrome (FXS). FXS is the most common genetic cause of intellectual disability and autism and is caused by loss of function of fragile X mental retardation protein (FMRP). I found that a disproportionate number of FMRP targets encode transcriptional regulators, particularly chromatin-associated proteins. In addition, I discovered that the loss of FMRP results in widespread chromatin misregulation and aberrant transcription. Finally, I demonstrated that the small molecule inhibitor Jq1 which blocks chromatin binding of the BET family of proteins alleviated many of the transcriptional changes and behavioral phenotypes associated with FXS. Through this work, I elucidated a novel causative mechanism of epigenetic disruption underlying FXS and demonstrated that targeting transcription may provide new treatment approaches. This work was published in Cell and included in a patent.

  • Kee, J., Thudium, S., Renner, D.M., Glastad, K., Palozola, K., Zhang, Z., Li, Y., Lan, Y., Cesare, J., Poleshko, A., Kiseleva, A.A., Truitt, R., Cardenas-Diaz, F. L., Zhang, X., Xie, X., Kotton, D. N., Alysandratos, K. D., Epstein, J.A., Shi, P.Y., Yang, W., Morrisey, E., Garcia, B. A., Berger, S. L., Weiss, S. R., Korb, E. SARS-CoV-2 protein encoded by ORF8 contains a histone mimic that disrupts chromatin regulation. Nature. (PMC in progress)
  • Thudium S, Palozola K, L’Her E, Korb E. Identification of a transcriptional signature found in multiple models of ASD and related disorders. Genome Research. (PMC in progress)
  • Korb, E., Herre, M., Zucker-Scharff, I., Allis, C.D., Darnell, RB. 2017. Excess translation of epigenetic regulators contributes to Fragile X Syndrome and is alleviated by Bd4 inhibition. Cell. (PMC5740873)
  • Inquimbert, P., Moll, M., Latremoliere, A., Tong, C.K., Wang, J., Sheehan, G.F., Smith, B.M., Korb, E., Athie, M.C.P., Babaniyi, O., Ghasemlou, N., Yanagawa, Y., Allis, C.D., Hof, P.R., Scholz, J. 2018. NMDA Receptor activation underlies the loss of spinal dorsal horn neurons and the transition to persistent pain after peripheral nerve injury. Cell Rep. (PMC62761118)

Epigenetic regulation of information storage in the brain

While chromatin regulation is crucial for the mechanisms underlying memory formation, the role of many chromatin-associated proteins in the context of neuronal function remains unclear. During my postdoctoral fellowship, I focused on Brd4, which binds acetylated histones. Despite the increasing use of Brd4 inhibitors as therapeutics, it had never been examined in the brain. I found that specific synaptic signals which leads to enhanced binding of Brd4 to histones to activate transcription of key neuronal genes that underlie memory formation. The loss of Brd4 function affects synaptic protein content, which results in memory deficits in mice and decreases seizure susceptibility. Thus, Brd4 provides a critical and previously uncharacterized link between neuronal activation and the transcriptional responses that occur during memory formation. This work has implications for the use of BET inhibitors in clinical settings and in possible treatments for epilepsy.

I also contributed to work examining additional mechanisms linking epigenetic regulation of transcription to behavioral responses to experience. This work from our collaborators in the lab of Dr. Eric Nestler (Ichan School of Medicine at Mount Sinai), examined the role of the ACF chromatin remodeling complex in depression. I investigated mechanisms controlling activity-dependent changes in expression of ACF. Together, these projects advanced our understanding of the link between neuronal signaling and epigenetic regulation underlying animal behavior both in normal conditions and in the context of mental health disorders. Finally, as an independent investigator, we published a review on the links between chromatin and plasticity mechanisms in the brain.

  • Korb, E., Herre, M., Zucker-Scharff, I., Darnell, RB., Allis, C.D. 2015. BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice. Nat. Neuro. (PMC4752120)
  • Herre, M., Korb, E. The chromatin landscape of neuronal plasticity. Curr. Opin. Neurobiol. (PMID: 31174107)
  • Sun, H., Damez-Werno, D.M., Scobie, K.M., Shao, N., Dias, C., Rabkin, J., Koo, J.W., Korb, E., Bagot, R.C., Ahn, F.H., Cahill, M., Labonte, B., Mouzon, E., Heller, E.A., Cates, H., Golden, S.A., Gleason, K., Russo, S.J., Andrews, S., Neve, R., Kennedy, P.J., Maze, I., Dietz, D.M., Allis, C.D., Turecki, G., Varga-Weisz, P., Tamminga, C., Shen, L., Nestler. E.J. 2015. ACF chromatin remodeling complex mediates stress-induced depressive-like behavior. Nat. Med. (PMC4598281)

Linking the synapse to the nucleus.

During my graduate school research, I sought to elucidate previously unexamined mechanisms regulating learning and memory. I focused on a protein that is critical for memory formation and synaptic plasticity, the activity-regulated cytoskeletal protein. Arc expression is robustly induced by activity, and Arc protein localizes both to active synapses and the nucleus. While its synaptic function had been examined in great detail, it was not clear why or how Arc is localized to the nucleus. I identified distinct regions of Arc that control its localization, including a nuclear localization signal, a nuclear retention domain, and a nuclear export signal. Arc localization to the nucleus regulates transcription, PML nuclear bodies, synaptic strength, and homeostatic plasticity. This was the first demonstration that Arc was important in regulating transcription and one of the first indications that PML bodies play an important role in neurons.

Our lab has undertaken projects examining other pathways that link external signals to responses within the nucleus. As part of a collaboration with Dr. Steven Josefowicz at Weill Cornell Medical School, we examined a previously unexplored histone modification, histone H3.3 serine 31 phosphorylation (H3.3S31ph). We demonstrated that in neurons H3.3S31ph is rapidly and robustly induced in neurons in response to synaptic stimulation. This was critical in expanding finding to additional cell types and systems beyond an immune cell response and was recently published in Nature.

  • Korb, E., Wilkinson, C. L., Delgado, R.N., Lovero, K.L., Finkbeiner, S. 2013. Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity. Nat. Neuro. 16(7), 874-83. (PMC3703835)
  • Korb, E., Finkbeiner, S. 2011. Arc in synaptic plasticity: from gene to behavior. Trends Neurosci. 34, 591-8. (PMC3207967)
  • Korb, E., Finkbeiner, S. 2013. PML in the Brain: From Development to Degeneration. Frontiers in Molecular and Cellular Oncology. 17, 242. (PMC3775456)
  • Armache, A., Yang, S., Martinez de Paz, A., Robbins, L.E., Durmaz, C., Yeong, J.Q., Ravishankar, A., Daman, A.W., Ahimovic, D.J., Klevorn, T., Yue, Y., Arslan, T., Lin, S., Panchenko, T., Hrit, J., Wang, M., Thudium, S., Garcia, B.A., Korb, E., Armache, K., Rothbart, S.B., Hake, S.B., Allis, C.D., Li H., Josefowicz, S.Z. 2020. Histone H3.3 phosphorylation amplifies stimulation-induced transcription. Nature. 583(7818), 852-857. (PMC75175895)

Research Interest

The Korb lab works at the intersection of neuroscience and epigenetics. Epigenetic regulation is extremely important in neuronal function and contributes to the creation of new memories, our ability to adapt to our environment, and numerous neurological disorders. We try to understand how the world around us can influence gene expression in our neurons to allow us to learn, adapt, and become the people we are today.
In the lab, we focus on chromatin and its role in neuronal function. Chromatin is the complex of DNA and proteins called histones, which package our DNA into complex structures and control access to our genes. To study the role of histones in neuronal function and in disorders such as autism, we combine methods such as microscopy, bioinformatics, biochemistry, behavioral testing, and more. We have multiple areas of research in the lab, all focused on the study of chromatin and how it regulates neuronal function and neurodevelopmental disorders.

George Burslem, Ph.D.

Targeted Protein Degradation
Approximately 75% of the proteome is considered undruggable by traditional small molecule inhibition approaches. As an LLS postdoctoral fellow at Yale, I contributed to the development and application of Proteolysis Targeting Chimera (PROTACs) – heterobifunctional small molecules which recruit an E3 ligase to a protein target, resulting in target ubiquitination and subsequent degradation via the proteasome. This enables small molecule induced degradation of disease relevant proteins in native systems including in vivo. One of my contributions was to expand this approach to transmembrane proteins (specifically receptor tyrosine kinases) which are not endogenously degraded via the proteasome but can be degraded in this manner under small molecule control. The PROTAC approach has also been applied to crucial targets (BCR-Abl and FLT-3 ITD) in hematological malignancies demonstrating the power of the PROTAC approach for drug discovery and revealing previously unknown scaffolding roles of these kinases.
– Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery, G.M. Burslem and C.M. Crews, Cell, 2020, 181, 102. PMCID: PMC7319047
– Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-mediated Targeted Protein Degradation, G.M. Burslem, A. Reister-Schultz, D.P. Bondeson, C. Eide, S. Savage, B. Druker and C.M. Crews, Cancer Research, 2019, 79. 4744. PMCID: PMC6893872
– Enhancing Antiproliferative Activity and Selectivity of a FLT-3 Inhibitor by Proteolysis Targeting Chimera Conversion, G.M. Burslem, J. Song, X. Chen, J. Hines and C.M. Crews, J. Am. Chem. Soc., 2018, 140, 16428. PMID: 30427680
– The Advantages of Targeted Protein Degradation over Inhibition: an RTK Case Study, G.M. Burslem, B.E. Smith, A. Lai, S. Jaime-Figueroa, D. McQuaid, D.P. Bondeson, M. Toure, H. Dong, Y. Qian, J. Wang, A.P. Crew, J. Hines and C. M. Crews, Cell Chemical Biology, 2018, 25, 67. PMCID: PMC5777153

HIF-1α/p300 Inhibition
Mammalian cells have developed an elaborate pathway for oxygen sensing with a key player in this pathway being hypoxia inducible factor 1α (HIF-1α). Under hypoxic conditions, HIF-1α accumulates, heterodimerizes and translocated to the nucleus where it forms a protein-protein interaction with p300. This complex is transcriptionally active resulting in the hypoxic response and resupply of oxygen to the hypoxic tissue. This pathway is crucial for growth and development but is also exploited by solid tumors to enable growth to continue after exhaustion of their oxygen supply. As a graduate student, I focused on elucidating the molecular recognition between HIF-1α and p300 using biophysical and biochemical approaches before applying that knowledge to develop the first biophysically characterized inhibitors of this protein-protein interaction. Furthermore, this project led to the identification of novel peptide and protein aptamer inhibitors of the HIF-1α/p300 interaction via phage display and a novel class of chemical probes which incorporates both natural and unnatural recognition elements to provide enhanced selectivity and potency.
– Hypoxia Inducible Factor as a Model for Studying Inhibition of Protein-Protein Interactions, G.M. Burslem, H.F. Kyle, A.S. Nelson, T.A. Edwards, A.J. Wilson, Chemical Science, 2017, 8, 4188. PMCID: PMC5576430
– Towards “Bionic” Proteins: Replacement of Continuous Sequences from HIF-1α with Proteomimetics to Create Functional p300 Binding HIF-1α Mimics, G.M. Burslem, H.F. Kyle, A. L. Breeze, T.A. Edwards, S.L. Warriner, A. S. Nelson and A.J. Wilson, Chem. Commun., 2016, 52, 5421. PMCID: PMC4843846
– Small molecule proteomimetic inhibitors of the HIF-1α/p300 protein-protein interaction, G.M. Burslem, H. Kyle, A. Breeze, T.A. Edwards, A. Nelson, S.L. Warriner and A.J. Wilson, ChemBioChem, 2014, 15, 1083. PMCID: PMC4159589
– Exploration of the HIF-1α/p300 binding interface using peptide and adhiron phage display technologies to locate binding hot-spots for inhibitor development, H. F. Kyle, K. F. Wickson, J. Stott, G. M. Burslem, A. L. Breeze, D. C. Tomlinson, S. L. Warriner, A. Nelson, A. J. Wilson and T. A. Edwards, Mol. Biosyst., 2015, 11, 2738. PMID: 26135796

Modulating Protein-Protein Interactions
There are an estimated 650,000 pairwise protein-protein interactions in the human interactome and these interactions are implicated in all biological pathways. As such, the ability to modulate protein-protein interactions with chemical probes can provide unique insights in the functional roles of proteins and their binding partners. Over my career I have developed chemical biology approaches to both inhibit and induce protein-protein interactions as tool compounds and therapeutic approaches. An attractive approach to the inhibition of protein-protein interactions is to develop molecules which mimic a portion of one of protein binding partners and thus preferentially occupy the binding site on the other. Peptides are capable of doing this but must pay a significant entropic penalty to adopt the required conformation due to their inherent flexibility. One approach to combat this is to pre-organize the peptide into the desired conformation by chemically “stapling” it. Another approach is to develop small molecule mimetics capable of recapitulating the recognition elements of a protein/peptide but with less conformational flexibility. I have applied both of these techniques to generate inhibitors of a variety of protein-protein interactions including p53/hDM2, Bcl-XL/BID and RNase S-peptide/S-protein. Furthermore, protein-protein interactions can be induced by small molecules known as molecular glues which we have employed to stabilize interactions between Cereblon and IKZF1. We have also demonstrated the ability to induce protein-protein interactions between various proteins using heterobifunctional compounds.
– Double Quick, Double “Click” Reversible Peptide “Stapling”, C.M. Grison, G.M. Burslem, J.A. Miles, L. Pilsl, D.J. Yeo, S.L. Warriner, M. E. Webb and A. J. Wilson, Chemical Science, 2017, 8, 5166. PMCID: PMC5618791
– Synthesis of Highly Functionalized Oligobenzamide Proteomimetic Foldamers by Late-Stage Introduction of Sensitive Groups, G.M. Burslem, H.F. Kyle, P. Prabhakaran, A. L. Breeze, T.A. Edwards, S.L. Warriner, A. Nelson and A.J. Wilson, Org. Biomol. Chem. 2016, 14, 3782. PMCID: PMC4839272
– Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure Degradation Relationships. G.M. Burslem*, P. Ottis, S. Jaime-Figueroa, A. Morgan, P.M. Cromm, M. Toure and C.M. Crews*, ChemMedChem, 2018, 12, 1508 (*Co-corresponding authors). PMCID: PMC6291207
– Lessons on Selective Degradation with a Promiscuous Warhead: Informing PROTAC Design, D.P. Bondeson, B.E. Smith, G.M. Burslem, A.D. Buhimschi, J. Hines, S. Jaime-Figueroa, J. Wang, B. Hamman, A. Ishchenko, C.M. Crews, Cell Chemical Biology, 2018, 25, 78. PMCID: PMC5777153

Epigenetic Chemical Biology
Epigenetic drug discovery provides a wealth of opportunities for the discovery of new therapeutics but has been hampered by low hit rates, frequent identification of false-positives, and poor synthetic tractability. Since establishing my laboratory at the University of Pennsylvania, we have endeavored to remedy the low hit rate in drug discovery efforts against epigenetic targets, by careful chemo-informatic analysis of active compounds and screening libraries. We have used the information gathered in these analysis to inform the design and synthesis of privileged compound collections for epigenetic chemical biology and probe discovery.
– Photochemical Synthesis of an Epigenetic Focused Tetrahydroquinoline Library, A.I. Green and G.M. Burslem, RSC Medicinal Chemistry, 2021, DOI: 10.1039/D1MD00193K
– Focused Libraries for Epigenetic Drug Discovery: The Importance of Isosteres, A.I. Green and G.M. Burslem, J. Med. Chem, 2021, 64, 7231-7240. PMID: 34042449
– Advances and Opportunities in Epigenetic Chemical Biology, J. Beyer, N. Raniszewski and G.M. Burslem, ChemBioChem, 2021, 22, 17-42. PMID: 32786101

Research Interest

The Burslem lab is interested in developing chemical tools to understand and modulate lysine post-translational modifications, specifically acetylation and ubiquitination. The laboratory is particularly interested in novel pharmacological approaches to modulate post-translational modifications which regulate gene expression and protein stability.

Rahul Kohli, M.D., Ph.D.

Elucidating and exploiting the mechanism of natural product macrocycle biosynthesis to make improved antibiotics. Many natural product antibiotics are brought to their bioactive conformations by cyclization. Macrocyclization rigidifies the small molecules to make them more effective at binding to their molecular targets. In my graduate work, I examined the natural product assembly lines of non-ribosomal peptide synthetases. In this work, I helped to establish that, rather than simply being responsible for unloading of the synthetase modules, the C-terminal domain of these assembly lines can catalyze release and macrocyclization of the natural products ref (a). After this initial discovery, I showed that this mechanism is broad ranging across a wide range of natural products spanning anti-infective and anti-cancer agents. We leveraged these advances to develop a chemoenzymatic approach to access alternative classes of related natural products (ref (b)), target new therapeutic areas (ref (c)), or improve antibiotic activity or specificity (ref (d)). This work demonstrates my abilities to decipher complex enzymatic reaction mechanisms.

Trauger JW, Kohli RM, Mootz HD, Marahiel MA, Walsh CT (2000) Peptide cyclization catalysed by the thioesterase domain of tyrocidine synthetase, Nature 407: 215-218.
Kohli RM, Burke MD, Tao J, Walsh CT (2003) Chemoenzymatic route to macrocyclic hybrid peptide/polyketide-like molecules, J Am Chem Soc 125: 7160-7161.
Kohli RM, Takagi J, Walsh CT (2002) The thioesterase domain from a nonribosomal peptide synthetase as a cyclization catalyst for integrin binding peptides, Proc Natl Acad Sci USA 99: 1247-1252 (PMC122175).
Kohli RM, Walsh CT, Burkart MD (2002) Biomimetic synthesis and optimization of cyclic peptide antibiotics, Nature 418: 658-661.

Targeting the SOS Pathway to combat antibiotic resistance. My clinical training has exposed me to the ever-increasing impact of antibiotic resistance and made it evident that “next generation” antibiotics only stall resistance. My involvement in making “next generation” antibiotics (see (1) above) made me realized the need to tackle the root cause, i.e., how antibiotic resistance arises. In this vein, we have focused on understanding how the DNA damage response of bacteria (also known as the SOS response) allows them to adapt to antibiotics or evolve and acquire resistance. Our detailed biochemical analyses (ref (a)) have allowed us to devise strategies for targeting the SOS response to potentiate antibiotics (ref (b)) and we have isolated first-in-class inhibitors of LexA (ref (c)). This work represents my lab’s effort to advance a new paradigm (ref (d)) in a field with great need for innovation.

Mo CY, Birdwell LD, Kohli RM (2014) Specificity Determinants for Autoproteolysis of LexA, a Key Regulator of Bacterial SOS Mutagenesis, Biochemistry 53:3158-68 (PMC4030785).
Mo CY, Manning SA, Roggiani M, Culyba MJ, Samuels AN, Sniegowski PD, Goulian M, Kohli RM (2016) Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics, mSphere 1:e00163-16 (PMC4980697).
Mo CY, Culyba MJ, Selwood T, Kubiak JM, Hostetler ZM, Jurewicz AJ, Keller PM, Pope AJ, Quinn A, Schneck J, Widdowson KL, Kohli RM (2018) Inhibitors of LexA Autoproteolysis and the Bacterial SOS Response Discovered by an Academic-Industry Partnership, ACS Infect Dis 4:349-359 (PMC5893282).
Merrikh H, Kohli RM (2020) Targeting Evolution to Inhibit Antibiotic Resistance, FEBS J, 287: 4341-4352 (PMC7578009).

Explaining the basis for targeted mutagenesis by DNA deaminases. My clinical experiences have highlighted the importance of understanding how diversity arises on both sides of the host-pathogen interface. As a clear example of our ability to integrate nucleic acid chemistry with enzyme mechanisms, my lab has made great strides in understanding how targeted and purposeful mutation is used to improve our immune defenses. Activation Induced Deaminase (AID) is the key driver of antibody maturation, catalyzing the targeted deamination of cytosine to generate uracil within the immunoglobulin locus. We have helped to decipher how targeting takes place at the molecular level, demonstrating how particular hotspots in the genome are targeted by AID and its APOBEC3 relatives (refs (a) and (c)) and how the enzyme can discriminate DNA from RNA (ref (b)). Most recently, we have leveraged this knowledge to develop small molecule controllable genomic base editors. This work demonstrates my success in manipulating enzymes to reveal mechanism and alter function.

Kohli RM, Abrams SR, Gajula KS, Maul RW, Gearhart PJ, Stivers JT (2009) A portable hotspot recognition loop transfers sequence preferences from APOBEC family members to activation-induced cytidine deaminase, J Biol Chem 284: 22898-22904 (PMC2755697).
Nabel CS, Lee JW ,Wang LC Kohli RM (2013) Nucleic acid determinants for selective deamination of DNA over RNA by activation-induced deaminase, Proc Natl Acad Sci USA 110: 14225–14230 (PMC3761612).
Gajula KS, Huwe PJ, Mo CY, Crawford DJ, Stivers JT, Radhakrishnan R, Kohli RM (2014) High-throughput mutagenesis reveals functional determinants for DNA targeting by activation-induced deaminase, Nucleic Acids Res 42: 9964-75 (PMC4150791).
Berríos KN, Evitt NH, DeWeerd RA, Ren D, Luo M, Barka A, Wang T, Bartman CR, Lan Y, Green AM, Shi J, Kohli RM (2021) Controllable genome editing with split-engineered base editors. Nat Chem Biol. 17:1262-1270.

Addressing the enigmatic mechanism of DNA demethylation. Despite the wealth of studies on the importance of 5-methylcytosine (mC) in mammalian genomes, the mechanism by which DNA can be demethylated has remained elusive. While high profile studies had suggested that deamination of mC or related analogs could be involved in DNA demethylation, the biochemical feasibility of this reaction had not been established. Further, with the discovery of TET family enzymes that can oxidize mC, new avenues for demethylation have been recently proposed. We were the first to show that enzymatic deamination of oxidized analogs of mC is a disfavored route for demethylation and that TDG can deplete 5-formylcytosine from genomes (ref (a)). We have also demonstrated that TET2 shows catalytic processivity (ref (b)), providing a mechanism for the generation of highly oxidized mC species despite the relative dearth of their precursors, uncovered new reactivities for TET enzymes (ref (c)), and helped to reveal new and unexpected DNA modifications which may mediate demethylation. Finally, we contributed to work led by Dr. Fraietta showing the clinical importance of TET2 in CAR-T therapy (ref (d)). This work demonstrates my role in helping to shape to the field’s current model for how methylation, deamination and oxidation collaborate to establish the epigenome.

Nabel CS, Jia H, Ye Y, Shen L, Goldschmidt HL, Stivers JT, Zhang Y, Kohli RM (2012) AID/APOBEC deaminases disfavor modified cytosines implicated in DNA demethylation, Nature Chem Biol 8:751-8 (PMC3427411).
Crawford DJ, Liu MY, Nabel CS, Cao XJ, Garcia BA, Kohli RM (2016) Tet2 Catalyzes Stepwise 5-Methylcytosine Oxidation by an Iterative and de novo Mechanism, J Am Chem Soc 138:730-3 (PMC4762542).
Ghanty U, Wang T, Kohli RM. (2020) Nucleobase Modifiers Identify TET Enzymes as Bifunctional DNA Dioxygenases Capable of Direct N-Demethylation, Angew Chem Int Ed, 59: 11312-11315 (PMC7332413).
Fraietta JA, Nobles CL, Sammons MA, Lundh S, Carty SA, Reich TJ, Cogdill AP, Morrissette JJD, DeNizio JE, Reddy S, Hwang Y, Gohil M, Kulikovskaya I, Nazimuddin F, Gupta M, Chen F, Everett JK, Alexander KA, Lin-Shiao E, Gee MH, Liu X, Young RM, Ambrose D, Wang Y, Xu J, Jordan MS, Marcucci KT, Levine BL, Garcia KC, Zhao Y, Kalos M, Porter DL, Kohli RM, Lacey SF, Berger SL, Bushman FD, June CH, Melenhorst JJ. (2018) Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells, Nature, 558: 307-312 (PMC 29849141).

Rational engineering of DNA modifying enzymes for epigenetic analysis and sequencing. Utilizing a structurally guided approach, we evolved the first TET variants that selectively stall oxidation at 5-hydroxymethylcytosine (hmC) (ref (a)). These modified enzymes offer a novel tool that is being applied to understand the role of 5-hydroxymethylcytosine, as distinct from the highly oxidized bases 5-formylcytosine and 5-carboxycytosine. In a similar vein, we have exploited our knowledge of APOBEC selectivity (ref (b)) to develop an enzymatic method to localize 5-hydroxymethylcytosine in genomic DNA (ref (c)). These advances demonstrate our success in harnessing structure-function insights into DNA modifying enzymes to apply them to reveal new biology.
Liu MY, Torabifard H, Crawford DJ, DeNizio JE, Cao XJ, Garcia BA, Cisneros GA, Kohli RM (2016) Mutations along a TET2 active site scaffold stall oxidation at 5-hydroxymethylcytosine. Nature Chem Biol, 3:181-187 (PMC5370579).
Schutsky EK, Nabel CS, Davis AKF, DeNizio JE, Kohli RM (2017) APOBEC3A efficiently deaminates methylated, but not TET-oxidized, cytosine bases in DNA. Nucleic Acids Res. 45:7655-7665 (PMC5570014).
Schutsky EK, DeNizio JE, Hu P, Liu MY, Nabel CS, Fabyanic EB, Hwang Y, Bushman FD, Wu H, Kohli RM. (2018) APOBEC-Coupled Epigenetic Sequencing permits low-input, bisulfite-free localization of 5-hydroxymethylcytosine at base resolution. Nature Biotech. 36: 1083–1090 (PMC6453757).
Caldwell BA, Liu MY, Prasasya RD, Wang T, DeNizio JE, Leu NA, Amoh NYA, Krapp C, Lan Y, Shields EJ, Bonasio R, Lengner CJ, Kohli RM, Bartolomei MS. (2021) Functionally distinct roles for TET-oxidized 5-methylcytosine bases in somatic reprogramming to pluripotency. Mol Cell. 81: 859-869 (PMC7897302).

Research Interest

While we conventionally think of genomic DNA as a simple polymer of A‘s, C‘s, G‘s, and T‘s, the chemistry of the genome is in fact far more interesting.

Our laboratory focuses on the DNA modifying enzymes that provide an added layer of complexity to the genome. These enzymes can be involved in the purposeful introduction of mutations or in the chemical modification of nucleobases, making DNA a remarkably dynamic entity. Many of these processes are at the heart of the battle between the immune system and pathogens or are central to epigenetics.

Our work can be broadly classified in two areas:

Enzymatic deamination, oxidation and methylation of cytosine bases, with a focus on AID/APOBEC DNA deaminases and TET oxygenases

Targeting Pathogen Pathways that Promote Evolution and Antibiotic Resistance, with a focus on the LexA/RecA axis governing the bacterial SOS response.

We utilize a broad array of approaches, which include 1) biochemical characterization of enzyme mechanisms, 2) chemical synthesis of enzyme probes, and 3) biological assays spanning bacteriology, immunology, and virology to study DNA modifying enzymes and pro-mutagenic pathways.

Our research program aims to understand diversity generating enzymes and pathways in vitro, to perturb their function in physiological settings, and to harness the biotechnological potential of these diversity-generating pathways.

Matt Weitzman, Ph.D.

Work in my lab addresses the dynamic interactions between viruses and host cells when their genomes are in conflict. My lab pioneered the study of cellular damage sensing machinery as an intrinsic defense to virus infection. We have studied the DNA damage responses with a range of human DNA viruses and identified distinct ways that they manipulate signaling networks and DNA repair processes. Studying DNA damage as part of the cellular response to infection has opened up a new area in the biology of virus-host interactions. It has also provided a platform for interrogating cellular pathways involved in recognition and processing of DNA damage. This work revealed that the MRN complex is the mammalian sensor of DNA breaks and viral genomes, and that it is required for efficient activation of ATM/ATR damage signaling.

Stracker, TH, Carson, CT and Weitzman, MD. (2002) Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature, 418, 348-352.
Carson, CT, Schwartz, RA, Stracker, TH, Lilley, CE, Lee, DV and Weitzman, MD (2003). The Mre11 complex is required for ATM activation and the G2/M checkpoint.  EMBO J, 22,6610-6620.
Lilley, CE, Carson, CT, Muotri, AR, Gage, FH and Weitzman, MD (2005). DNA repair proteins affect the HSV-1 lifecycle.  Proc Natl Acad Sci USA, 102, 5844-5849.
Lilley, CE, Chaurushiya, MS, Boutell, C, Everett, RD, and Weitzman, MD (2011). The intrinsic antiviral defense to incoming HSV-1 genomes includes specific DNA repair proteins and is counteracted by the viral protein ICP0. PLoS Pathog 7:e1002084. PMC3116817
Chaurushiya, MS, Lilley, CE, Aslanian, A, Meisenhelder, J, Scott, DC, Landry, S, Ticau, S, Boutell, C, Yates, JR, Schulman, BA, Hunter, T and Weitzman, MD (2012). Viral E3 ubiquitin-mediated degradation of a cellular E3: viral mimicry of a cellular phosphorylation mark targets the RNF8 FHA domain.  Mol Cell 46, 79-90. PMC3648639

I have had a long-standing interest in viral and host proteins that bind DNA and chromatin. As a postdoc I used biochemical approaches to identify a recognition sequence for the Rep protein of AAV within the site-specific integration site on chromosome 19 (AAVS1). I demonstrated that Rep proteins can mediate interaction between cellular and viral DNA to promote targeted integration. We have recently employed proteomic approaches to identify proteins associated with viral DNA genomes during infection, as well as the modifications that occur to chromatin on the host genome. We have analyzed histone post-translational modifications during virus infection and shown how these are altered by viruses. We recently discovered that the histone-like protein VII encoded by Adenovirus for packaging of its genome, can also affect the composition of cellular chromatin by retaining danger signals to overcome immune signaling. We are now interested in looking at how viruses impact genome and nuclear architecture and the effects this has on gene expression.

Weitzman, MD, Kyöstiö, SRM, Kotin, RM and Owens, RA (1994). Rep proteins of adeno-associated virus (AAV) mediate a complex formation between AAV DNA and the AAV integration site on human chromosome 19.  Proc Natl Acad Sci USA, 91, 5808-5812.
Kulej, K, Avgousti, DC, Weitzman, MD and Garcia, BA (2015). Characterization of histone post-translational modifications during virus infection using mass spectrometry-based proteomics. Methods 90, 8-20.
Avgousti, DC, Herrmann, C, Sekulic, N, Kulej, K, Petrescu, J, Molden, RC, Pancholi, NJ, Reyes, ED, Seeholzer, SH, Black, BE, Garcia, BA and Weitzman, MD (2016). A core viral protein binds host nucleosomes to sequester immune danger signals. Nature 535, 173-177. PMC4950998
Kulej, K, Avgousti, DC, Sidoli, S, Herrman C, Della Fera, AN, Kim ET, Garcia, BA and Weitzman, MD (2017). Time-resolved global and chromatin proteomics during Herpes Simplex Virus Type 1 (HSV-1) infection. Mol Cell Proteomics 16, S92-S107.
Reyes, RD, Kulej, K, Akhtar, LN, Avgousti, DC, Pancholi, NJ, Kim, ET, Bricker, D, Koniski, S, Seeholzer, SH, Isaacs, SN, Garcia, BA, and Weitzman, MD. Identifying host factors associated with DNA replicated during virus infection. (in press).

My lab is interested in cellular responses that restrict virus replication. APOBEC3 proteins belong to a family of cytidine deaminases that provide a line of defense against retroviruses and endogenous mobile retroelements. We were the first to show that human APOBEC3A (A3A) is a catalytically active cytidine deaminase, with a preference for ssDNA. We demonstrated that A3A is a potent inhibitor of endogenous retroelements such as LINE1, and also blocks replication of single-stranded parvoviruses such as AAV and MVM. We have also shown how the SAMHD1 protein limits replication of the DNA virus HSV-1. We discovered ways that cellular DNA repair proteins can act as species-specific barriers through their interaction with viral proteins.

Chen, H, Lilley, CE, Yu, Q, Lee, DV, Chou, J, Narvaiza, I, Landau, NR and Weitzman, MD (2006). APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons.  Curr Bio 16, 480-485.
Narvaiza, I, Linfesty, DC, Greener, BN, Hakata, Y, Pintel, DJ, Logue, E, Landau, NR, and Weitzman, MD (2009). Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase.  PLoS Pathog 5, e1000439. PMC2678267
Richardson, SR, Narvaiza, I, Planegger, RA, Weitzman, MD and Moran, JV (2014). APOBEC3A deaminates transiently exposed single-strand DNA that arises during LINE-1 retrotransposition.  eLife 3, e02008. PMC4003774
Kim, ET, White, TE, Brandariz-Nunez, A, Diaz-Griffero, F, and Weitzman, MD (2013). SAMHD1 restricts herpes simplex virus type 1 (HSV-1) in macrophages by limiting DNA replication.  J Virol 87, 12949-12956. PMC3838123
Lou, DI, Kim, ET, Shan, S, Meyerson, NR, Pancholi, NJ, Mohni, KM, Enard, D, Petrov, DA, Weller, SK, Weitzman, MD*, and Sawyer, SL (2016). An intrinsically disordered region of the DNA repair protein Nbs1 is a species-specific barrier to Herpes Simplex Virus 1 in primates.  Cell Host & Microbe 20, 178-188. (*Co-corresponding author)

Proteins that mutate viral genetic material must also be carefully regulated to prevent deleterious effects on the host genome. While studying antiviral functions for A3A we discovered that the enzyme can also act on the cellular genome, inducing DNA breaks and cell cycle arrest. We suggested therefore that APOBEC proteins cause genomic instability and contribute to malignancy, and we are now studying how they are regulated to prevent inappropriate mutations. This body of work demonstrates how studying virus-host interactions can lead to insights into fundamental processes that impact cellular genomic integrity. We have recently found A3A upregulated in a subset of human leukemias and demonstrated how this provides vulnerability for targeted cancer therapies.

Landry, S, Narvaiza, I, Linfesty, DC and Weitzman, MD (2011). APOBEC3A can activate the DNA damage response and cause cell cycle arrest.  EMBO Reports 12, 444-450. PMC3090015
Narvaiza, I, Landry, S, and Weitzman, MD (2012). APOBEC3 proteins and genome stability: The high cost of a good defense? Invited Extraview in Cell Cycle 11, 33-38.
Green, AM, Landry, S, Budagyan, K, Avgousti, D, Shalhout, S, Bhagwat, AS and Weitzman, MD (2016). APOBEC3A damages the cellular genome during DNA replication.  Cell Cycle 15, 998-1008. PMC4889253
Green, AM, Budagyan, K, Hayer, KE, Reed, MA, Savani, MR, Wertheim, GB and Weitzman, MD (2017). Cytosine deaminase APOBEC3A sensitizes leukemia cells to inhibition of the DNA replication checkpoint. Cancer Research (in press)

Research Interests

Our lab aims to understand host responses to virus infection, and the cellular environment encountered and manipulated by viruses. We study multiple viruses in an integrated experimental approach that combines biochemistry, molecular biology, genetics and cell biology. We have chosen viral models that provide tractable systems to investigate the dynamic interplay between viral genetic material and host defense strategies. We have used proteomic approaches to probe the dynamic interactions that take place on viral and cellular genomes during infection, and have uncovered ways that viruses manipulate histones and chromatin as they take control of cellular processes. The pathways illuminated are key to fighting diseases of viral infection, provide insights into fundamental processes that maintain genome instability, and have implications for the development of efficient viral vectors for gene therapy.

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