Golnaz Vahedi, Ph.D.

We have demonstrated for the first time that the epigenome of differentiated CD4 T cells is highly dynamic and extended these findings to human genetics to further our understanding of the epigenetic control in autoimmunity.
Johnson J.L. and Vahedi G.: Epigenome: a dynamic vehicle for transmitting and recording cytokine signalling. CSHL Perspectives, Cold Spring Harbor Laboratory Press 2017.
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D., Kurachi, M., Barnitz, R. A., Bartman, C., Bengsch, B., Huang, A. C., Schenkel, J. M., Vahedi, G., Haining, W. N., Berger, S. L., Wherry, E. J.: Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 2016.
Richard AC, Peters JE, Lee JC, Vahedi G, Schäffer AA, Siegel RM, Lyons PA, Smith KG.: Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network. Genome Medicine 76(8), July 2016.
Johnson, J. L., Vahedi, G.: Exploiting Chromatin Biology to Understand Immunology. Methods Enzymol 574: 365-83, 2016.
Vahedi, G., Kanno, Y., Furumoto, Y., Jiang, K., Parker, S. C., Erdos, M. R., Davis, S. R., Roychoudhuri, R., Restifo, N. P., Gadina, M., Tang, Z., Ruan, Y., Collins, F. S., Sartorelli, V., O’Shea, J. J.: Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature April 2015.
Vahedi, G., Kanno, Y., Sartorelli, V., O’Shea, J. J.: Transcription factors and CD4 T cells seeking identity: masters, minions, setters and spikers. Immunology 139(3): 294-8, 2013.
Vahedi, G., C. Poholek A, Hand, T. W., Laurence, A., Kanno, Y., O’Shea, J. J., Hirahara, K.: Helper T-cell identity and evolution of differential transcriptomes and epigenomes. Immunol Rev 252(1): 24-40, 2013.
Roychoudhuri, R., Hirahara, K., Mousavi, K., Clever, D., Klebanoff, C. A., Bonelli, M., Sciume, G., Zare, H., Vahedi, G., … , O’Shea, J. J., Restifo, N. P.: BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. Nature 498(7455): 506-10, 2013.
Vahedi, G., Takahashi, H., Nakayamada, S., Sun, H. W., Sartorelli, V., Kanno, Y., O’Shea, J. J.: STATs shape the active enhancer landscape of T cell populations. Cell 151(5): 981-93, 2012.
Vahedi, G., Faryabi, B., Chamberland, J. F., Datta, A., Dougherty, E. R.: Intervention in gene regulatory networks via a stationary mean-first-passage-time control policy. IEEE Trans Biomed Eng 55(10): 2319-31, 2008.

Research Interest

The Vahedi laboratory is multidisciplinary, integrating computational and experimental approaches to develop a single to collective cell understanding of gene regulation in immune cells in health and disease.
We exploit the epigenomics mapping of immune cells to understand the biological circuits that underlie immune responses and uncover the molecular basis of major inherited diseases mediated by these cells. Immune-mediated disorders such as psoriasis and type 1 diabetes result from a complex interplay of genetic and environmental factors. By mapping the epigenomic alterations associated with immune-mediated diseases, we aim to further our understanding of the role of environment in triggering autoimmunity.
Information encoded in DNA is interpreted, modified, and propagated as chromatin. The diversity of inputs encountered by immune cells demands a matching capacity for transcriptional outcomes provided by the combinatorial and dynamic nature of epigenetic processes. Advances in genome editing and genome-wide analyses have revealed unprecedented complexity of chromatin pathways involved in the immune response, offering explanations to long-standing questions and presenting new challenges.
We blend epigenomics, human genetics, immunology, and computational biology to pursue a new understanding of human immunology. We generate genome-wide maps of chromatin in relevant immune cells mostly T cells. We are interested in regulators of T cell development and also T cell engagement in autoimmune disorders such as psoriasis and type 1 diabetes. We use population-based assays with strong signal-to-noise ratios such as ChIP-seq, ATAC-seq, and RNA-seq in addition to cutting-edge single-cell assays such as single-cell (sc)ATAC-seq and scRNA-seq. As a result of our computational expertise, we also harvest the vast troves of big data that immunologists and other researchers are pouring into public repositories. Our data integrations rely on available computational pipelines. Furthermore, we develop novel computational techniques to fully understand the complexity of multidimensional epigenomics datasets in T cells.

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.

Previous Next
Close
Test Caption
Test Description goes like this