Posts classified under: Faculty

Penn Epigenetics > Faculty

Elizabeth Heller, Ph.D.

Contribution to Science

Proteomic characterization of inhibitory synapses. During doctoral training at The Rockefeller University under the mentorship of Dr. Nathaniel Heintz, I aimed to genetically tag and purify individual synapse types in the mammalian brain, in order to characterize their protein content using an innovative biochemical enrichment strategy coupled with high throughput proteomic analysis. In pursuit of this goal, I developed the first protocol for the specific biochemical isolation and characterization of the elusive inhibitory synapse.  We made a remarkable discovery, namely, that inhibitory synapses consist of structural proteins and ion channels, yet are completely lacking in the signaling molecules that comprise the major component of excitatory synapses.

Selimi F, Cristea IM, Heller E, Chait BT, Heintz N. Proteomic studies of a single CNS synapse type: the parallel fiber/purkinje cell synapse. PLoS Biol. 2009 Apr 14;7(4):e83. PubMed PMID: 19402746; PubMed Central PMCID: PMC2672601.
Heller EA, Zhang W, Selimi F, Earnheart JC, Ślimak MA, Santos-Torres J, Ibañez-Tallon I, Aoki C, Chait BT, Heintz N. The biochemical anatomy of cortical inhibitory synapses. PLoS One. 2012;7(6):e39572. PubMed PMID: 22768092; PubMed Central PMCID: PMC3387162.

Identification of critical period for sleep-consolidated spatial memory. During my undergraduate training I conducted an independent study under Dr. Ted Abel, aimed at elucidating the time course of sleep-induced memory formation in mice by examining memory deficits that result from sleep deprivation during discrete times following learning. We found that fear conditioning is blocked by sleep deprivation during a time period 5-10 hours post training, but unaffected by sleep deprivation for five hours immediately following training. This finding provided critical insights into the time-course of sleep-induced memory consolidation.

Graves LA, Heller EA, Pack AI, Abel T. Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning. Learn Mem. 2003 May-Jun;10(3):168-76. PubMed PMID: 12773581; PubMed Central PMCID: PMC202307.

Locus-specific epigenetic editing for the study of addiction and depression. My postdoctoral research aimed to investigate the causal molecular mechanisms by which chromatin modifications contribute to reward-related pathology in the mammalian brain. There is a preponderance of compelling evidence implicating epigenetic modifications in the pathology of addiction and depression, in both human patients and animal models, yet previous studies have been unable to distinguish between the mere presence and the functional relevance of epigenetic modifications at relevant loci. To elucidate the molecular function of epigenetic regulation relevant to reward pathology, I have developed the use of engineered transcription factors to deliver histone modifications to a specific gene of interest in reward-related regions of the mammalian brain (major publications listed in Personal Statement).
Identification of cellular and molecular mechanisms underlying addiction and stress. In addition to pursuing my main postdoctoral research project, described above, I have also worked with others both inside and outside of the Nestler lab to investigate the molecular basis of drug addiction. For example, I have studied the role of serum- and glucocorticoid-inducible kinase 1 (SGK1) in regulating morphine and cocaine reward, and found that while its transcription and activity are upregulated in vivo by morphine and cocaine, exogenous SGK1 overexpression causes opposite behavioral responses to these two drugs. I have also contributed to several additional studies on the epigenetics of addiction, such as the role of nucleosome remodeling and the Sirtuin family of histone deacetylase.

Ferguson D, Koo JW, Feng J, Heller E, Rabkin J, Heshmati M, Renthal W, Neve R, Liu X, Shao N, Sartorelli V, Shen L, Nestler EJ. Essential role of SIRT1 signaling in the nucleus accumbens in cocaine and morphine action. J Neurosci. 2013 Oct 9;33(41):16088-98. PubMed PMID: 24107942; PubMed Central PMCID: PMC3792451.
Cates HM, Thibault M, Pfau M, Heller E, Eagle A, Gajewski P, Bagot R, Colangelo C, Abbott T, Rudenko G, Neve R, Nestler EJ, Robison AJ. Threonine 149 phosphorylation enhances ΔFosB transcriptional activity to control psychomotor responses to cocaine. J Neurosci. 2014 Aug 20;34(34):11461-9. PubMed PMID: 25143625; PubMed Central PMCID: PMC4138349.
Koo JW, Lobo MK, Chaudhury D, Labonté B, Friedman A, Heller E, Peña CJ, Han MH, Nestler EJ. Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition. Neuropsychopharmacology. 2014 Oct;39(11):2646-53. PubMed PMID: 24853771; PubMed Central PMCID: PMC4207344.
Heller EA, Kaska S, Fallon B, Ferguson D, Kennedy PJ, Neve RL, Nestler EJ, Mazei-Robison MS. Morphine and cocaine increase serum- and glucocorticoid-inducible kinase 1 activity in the ventral tegmental area. J Neurochem. 2015 Jan;132(2):243-53. PubMed PMID: 25099208; PubMed Central PMCID: PMC4302038.

Research Interest

The Heller Lab studies the mechanisms by which remodeling of the epigenome leads to aberrant neuronal gene function and behavior.  To approach this problem, we directly manipulate histone and DNA modifications at specific genes in vivo, using viral delivery of epigenetic editing tools.  We focus on uncovering the mechanisms by which chromatin modifications interact with the transcriptional machinery following exposure to psychostimulants, such as drugs of abuse and stress. Because the behavioral disease traits of addiction and depression persist long after cessation of the harmful experience,  stable epigenetic remodeling is an attractive mechanism for such long-lasting effects and presents an intriguing target for therapeutic intervention.

Eric-Joyce

Eric F. Joyce, Ph.D.

Contribution to Science

We have generated custom Oligopaint probes to precisely target population-defined domains known as TADs in single cells and, using high- and super-resolution microscopy, found evidence for extensive heterogeneity across individual alleles. As this has implications for gene regulation, we discovered that the expression of genes at TAD boundaries are particularly sensitive to reduced cohesin levels in pathological cohesin dysfunction such as in cohesinopathies like Cornelia De Lange Syndrome. We further found that cohesin promotes stochastic boundary bypass between domains for proper expression of boundary-proximal genes. More recently, we found that co-depletion of NIPBL and WAPL, two opposing regulators of cohesin, rescues chromatin misfolding and gene misexpression, consistent with a model in which cohesin levels are balanced by its activity on chromatin.

Research Interest

Our laboratory studies the spatial organization of the genome. We use a combination of cellular, molecular, genetic, and computational tools to elucidate how the structure and position of chromosomes within the nucleus is established and inherited across cell divisions, and how dysfunctional organization contributes to genome instability and disease. We also develop and utilize new technologies that use fluorescent in situ hybridization (FISH) to interrogate chromosome structure at single-cell resolution.

Mitchell A. Lazar, M.D., Ph.D.

Contribution to Science

•Discovery of thyroid hormone receptors and their mechanism of repression.

• Discovery of Nuclear Receptor Corepressor Complexes.

• Elucidation of physiological Roles of Nuclear Receptor Corepressors and HDAC3.

• Discovery of REV-ERB and mechanisms of circadian regulation of transcription and metabolism.

• Identification and characterization of PPAR g in Adipose Biology.

Research Interest

The goal of the Lazar lab is to understand the transcriptional regulation of circadian rhythms and metabolism both in normal physiology and in  metabolic diseases such as diabetes and obesity. The focus is on nuclear receptors and HDAC3-containing corepressor complexes, whose functions are interrogated using a combination of genomic, proteomic, bioinformatic, and metabolic phenotyping methods.  Of particular interest are the circadian REV-ERB nuclear receptors, which are transcriptional repressors that function in the circadian clock and coordinate biological rhythms of metabolism in liver, adipose, and other tissues. Another focus is on nuclear receptor PPARg, a key transcriptional link between obesity and diabetes which functions as the master regulator of adipocyte biology and whose ligands have potent antidiabetic activity. Nuclear receptors corepressors and HDAC3 are also of great interest as an integrators of the activities of nuclear receptors and other transcription factors, with tissue-specific functions that protect from challenges to the circadian, nutritional, and thermal environment.

Mia Levine, PhD

Mia Levine, Ph.D.

Contribution to Science

The evolution of young genes via de novo- and duplication- based mechanisms
Evolutionary mechanisms of innovation at the molecular level are numerous. Codons diverge, regulatory elements arise and degenerate, and new genes are born. These signatures of adaptive evolutionary change are frequently species-restricted. My PhD research identified very young genes that harbor no homology to exons in related genomes. In contrast to classic mechanisms of novel gene formation like gene duplication, these de novo genes arise instead from fortuitous sequence evolution at noncoding DNA. These genes exhibited testis-biased expression and signatures of adaptive evolution, implicating male germline processes as potent agents of selection of these rare mutations. This publication was the first to describe such de novo genes that have since been documented in a wide array of taxa, including humans. My postdoctoral research focused instead on gene duplication as a potent mechanism of adaptive diversification. A shared domain structure between parent and daughter proteins facilitated my goal to identify lineage-specific innovations in proteins that package DNA. Prior to my research, the Heterochromatin Protein 1 (HP1) gene family was thought to encode between 2 and 5 members across eukaryotes. I discovered 22 new HP1 members in Drosophila. These 22 paralogs were all born less than 20 million years ago. Nevertheless, the number of HP1 genes per species remains relatively constant. This revolving door of gene replacement implicates conserved, currently undefined chromatin functions encoded by unconserved components recurrently generated by gene duplication.

Levine, M.T., C. D. Jones, A. D. Kern, H. A. Lindfors, and Begun, D.J. (2006) Novel genes derived from noncoding DNA in Drosophila melanogaster are frequently X-linked and exhibit testis-biased expression.Proceedings of the National Academy of Sciences 103: 9935-9939. PMCID: PMC1502557.
Levine, M.T., McCoy, C. Vermaak. D., LeeY.C.G, Hiatt, M.A., Matsen, F.A., and H.S. Malik (2012) Phylogenomic analysis reveals dynamic evolutionary history of the Drosophila Heterochromatin Protein 1 (HP1) gene family.  PLOS Genetics8(6): e1002729. PMCID: PMC3380853.

Adaption to novel environments at DNA packaging proteins

melanogaster, like humans, evolved in Africa but more recently invaded the New World and established populations from tropical to temperate climates. These geographically structured populations are panmictic (randomly mating), so any genotypic or phenotypic differences observed are likely the product of fitness variation across environments, i.e., natural selection. This spatially-structured system therefore presents a unique opportunity to elucidate the molecular basis of adaptation. I have taken both whole genome- and single locus- approaches. In one report, genomic DNA fromD. melanogastertropical and temperate populations from both Australia and the US were hybridized to whole-genome tiling arrays from which we inferred geographic sequence divergence (allele frequency variation) based on geographically structured differences in probe intensities. Our analysis demonstrated that a remarkably large fraction of the D. melanogaster genome has been targeted by spatially-varying positive selection. Our whole-genome analysis also uncovered many previously unsuspected biological functions associated with adaptation to novel environments. One of the most intriguing of these functions was chromatin binding. In light of the extensive data on the environment sensitivity of chromatin dynamics, I was especially interested in the unexplored role that chromatin-remodeling factors play in adaptation to novel habitat. Under one model, chromatin-remodeling factors evolve to maintain chromatin structure that is perturbed by environmental fluctuations. I focused primarily on the Polycomb Group genechameau. I discovered a linear relationship between latitude and allele frequency at several SNPs in both the US and Australian populations, which represent independent colonization events. Moreover, an amino acid-changing SNP predicted variation in tolerance to freezing temperatures. These data strongly implicated the action of natural selection and introduced chromatin-remodeling factors as a potentially rich source of adaptive genetic variation. Inspired by the observation that chromatin-based gene regulation can span more than one promoter, I also tested the hypothesis that adaptive expression variation across latitudinal gradients spans physically linked genes. I found that gene “neighborhoods” (of up to 15 genes), rather than single genes, exhibit adaptive transcriptional profiles, consistent with the notion that chromatin factors regulate adaptive expression variation across space.
Turner, L.T., Levine, M.T., and Begun, D.J. (2008). Genomic analysis of adaptive differentiation in Drosophila melanogaster.Genetics 179: 475-485. PMCID: PMC2390623.
Levine, M.T. and Begun, D.J. (2008). Evidence of spatially varying selection at four chromatin-remodeling loci inDrosophila melanogaster. Genetics 179: 455-473. PMCID: PMC2390624.
Levine, M.T., Eckert, M., and D.J. Begun (2011) Whole genome expression plasticity across tropical and temperateDrosophila melanogaster populations from eastern Australia. Molecular  Biology and Evolution 28: 249–256. PMCID: PMC3002243.

Evolutionary and functional diversification of essential DNA packaging proteins
Conserved nuclear proteins support conserved nuclear processes. Yeast and humans, for example, share essential, homologous chromatin proteins that package eukaryotic DNA and support shared, essential functions like chromosome segregation and telomere integrity. These cellular processes, however, also rely on unconserved molecular machinery. A surprisingly large fraction of essential genes that encode chromatin proteins evolve rapidly. My dissertation documented early evidence of this paradoxical phenomenon. The Dosage Compensation Complex (DCC) is responsible for equalizing X-linked gene dosage via chromatin remodeling of the single male X chromosome.  Loss of function at DCC genes is lethal. I discovered population genetic evidence of positive selection at four of the five DCC complex components. Continuing this theme during my postdoctoral research, I uncovered the essential function of the Heterochromatin Protein 1 paralog, HP1E. HP1E is required for faithful segregation of paternal DNA during the first embryonic mitosis. Nevertheless, a subset of Drosophila species apparently persists without HP1E. I discovered that in D. melanogaster not all paternal chromosomes are equally vulnerable to chromatin bridging during the first embryonic mitosis—the heterochromatin-rich sex chromosomes are more likely to mis-segregate than the large autosomes. Intriguingly, over evolutionary time major rearrangements of these same sex chromosomes co-occur with the pseudogenization of HP1E in the obscura group of Drosophila. These data support a model under which karyotype evolution rendered dispensable a once-essential gene. My findings thus provided a neat hypothesis to resolve the apparent paradox of HP1E’s essentiality in D. melanogaster together with its loss in related species.

Levine, M.T., Holloway, A.K., Arshad, U., and Begun, D.J. (2007) Pervasive and largely lineage-specific adaptive protein evolution in the dosage compensation complex of Drosophila melanogaster.Genetics 177: 1959–1962. PMCID: PMC2147993.
Levine, M.T. and H.S. Malik (2013) A rapidly evolving genomic toolkit of Drosophila heterochromatin.Fly 7: 137-141. PMCID: PMC4049844.
Levine, M.T., Vander Wende, H., and H.S. Malik (2015) Mitotic fidelity requires transgenerational action of a testis-restricted HP1.eLife 4: e07378. PMCID: PMC4491702

Research Interest

Chromatin proteins package our genomic DNA. Essential, highly conserved cellular processes rely on this genome compartmentalization, yet many chromatin proteins are wildly unconserved over evolutionary time. We study the biological forces that drive chromatin protein evolution and the functional consequences for chromosome segregation, telomere integrity, and genome defense.

Ronen Marmorstein, Ph.D.

Contribution to Science

1. My laboratory has pioneered the structure-function analysis of histone acetyltransferases (HATs) and continues to make seminal contributions in this area. Specifically, my laboratory determined the first crystal structure of a type A HAT and characterized its mechanism of catalysis, and the first to describe the mode of histone substrate binding by a HAT. My laboratory has extended our studies to the broader family of N- acetyltransferases including the non-histone lysine acetyltransferases (KATs) and the N-amino acetyltransferases (NATs). We have uncovered important molecular signatures that distinguish HATs, KATs and NATs. My laboratory has also contributed to the development of acetyltransferase inhibitors. The vast majority of the human proteome is acetylated in a functionally important manner and alterations occur in human diseases. This suggests that protein acetylation may rival protein phosphorylation as a biologically important protein modification and that KATs and NATs represent important therapeutic targets.
a. Deng, S., McTiernan, N., Wei, X., Arnesen, T. and Marmorstein, R. Molecular basis for N-terminal acetylation by human NatE and its modulation by HYPK, (2020) Nature Comm., 11: 14584-14587. PMID32042062: PMCID: PMC7010799
b. Deng, S., Pan, B., Gottlieb, L. and Marmorstein, R. Molecular basis for N-terminal alpha-synuclein acetylation by human NatB. (2020) eLife. 9: e57491. PMID32885784
Deng, S., Gottlieb, L., Pan, B., Supplee, J., Wei, Xuepeng, Petersson, E.J. and Marmorstein, R., Molecular mechanism of N-terminal acetylation by the ternary NatC complex. (2021) Structure, S0969-2126. PMID34019809
Gottlieb, L., Guo, L., Shorter, J. and Marmorstein, R. N-alpha-acetylation of Huntingtin protein increases its propensity to aggregate. (2021) J. Biol. Chem., 31: 101363-. PMID34732320

2. My laboratory is studying the molecular basis for how chromatin is assembled and maintain by histone chaperone complexes. We have focused on the binding and histone deposition of H3/H4 complexes by the ASF1 and VPS75 proteins and the multi-subunit HIRA complex, which specifically deposits the histone H3 variant, H3.3, in a replication independent manner. Histone H3.3 is deposited at active genes, after DNA repair and in certain forms of heterochromatin in non-proliferating senescent cells, and recurrent H3.3 mutations are found in pediatric glioblastoma and dysregulation of H3.3-specific activities in tumor growth and leukemia exemplifies the necessity for proper regulation of H3.3-specific deposition pathways. Together with the Peter Adams laboratory we have pioneered a molecular understanding of the HIRA complex highlighting the particular importance of the HIRA and Ubn1 subunits of H3.3-specific activities.
a. Ricketts, M.D., Frederick, B., Hoff. H., Tang, Y., Schultz, D.C. Rai, T.S., Vizioli, M.G. Adams, P.D. and Marmorstein, R. Ubinuclein-1 confers histone H3.3-specific binding specificity by the HIRA histone chaperone complex. (2015) Nature Commun. 6:7711-. PMID: 26159857: PMCID: PMC4509171
b. Haigney, A., Ricketts, M. D. and Marmorstein, R. Dissecting the Molecular Roles of Histone Chaperones in Histone Acetylation by Type B Histone Acetyltransferases (HAT-B), (2015) J. Biol. Chem., 290:30648-30657. PMID: 26522166: PMCID: PMC4683284
c. Ray-Gallet, D., Ricketts, M.D., Sato, Y., Gupta, K., Boyarchuk, E., Senda, T., Marmorstein, R., and Almouzni, G. Functional activity of the H3.3 histone chaperone complex HIRA requires trimerization of the HIRA subunit. (2018) Nat. Commun. 9:3103. PMID:30082790: PMCID: PMC6078998
d. Ricketts, M.D., Dasgupta, N., Fan, J., Han, J., Gerace, M., Tang, Y., Black, B.E., Adams, P.D. and Marmorstein, R. The HIRA histone chaperone complex subunit UBN1 harbors H3/H4 and DNA binding activity. (2019) J. Biol. Chem., 294: 9239-9259. PMID:31040182; PMCID: PMC6556585

3. My laboratory has leveraged our expertise in biochemistry and X-ray crystallography with small molecule screening for structure-based Inhibitor development for therapy of melanoma and other cancers. There is a particular interest in melanoma and the laboratory had developed inhibitors to several important oncogenic kinases in melanoma including BRAF, PI3K, PAK1 and S6K1. The laboratory has also targeted the oncoproteins E7 and E6 from human papillomavirus (HPV), the causative agent of a number of epithelial cancers, and a significant portion of head and neck cancers. These studies have important implications for therapy.
a. Qin, J., Rajaratnam, R., Feng, L., Salami, J., Barber-Rotenberg, J.S., Domsic, J., Reyes-Uribe, P., Liu, H., Dang, W., Berger, S.L., Villanueva, J., Meggers, E. and Marmorstein, R. Development of organometallic S6K1 inhibitors. (2015) J. Med. Chem. 58:305-314. PMID: 25356520; PMCID: PMC4289024
b. Grasso, M., Estrada, M.A., Ventocilla, C., Samanta, M., Maksimoska, J., Villanueva, J., Winkler, J.D. and Marmorstein, R. Chemically linked vemurafenib inhibitors promote an inactive BRAFV600E conformation. (2016) ACS Chem. Biol. 11: 2876-2888. PMID: 27571413: PMCID: PMC5108658
c. Emtage, R.P., Schoeberger, M.J. Fergusion, K.M., and Marmorstein, R. Intramolecular autoinhibition of Checkpoint Kinase 1 is mediated by conserved basic motifs of the C-terminal Kinase Associated-1 domain. (2017) J. Biol. Chem. 292:19024-19033. PMID:28972186: PMCID: PMC5704483
d. Grasso, M., Estrada, M.A., Berrios, K.N., Winkler, J.D. and Marmorstein, R. N-(7-Cyano-6-(4-fluro-3-(2-(3-(trifluoromethyl)phenyl)acetamido)phenoxy)benzo[d]thiazol-2-yl)cyclopropanecarboxamide (TAK632) promotes inhibition of BRAF through the induction of inhibited dimers. (2018) J. Med. Chem. 61:5034-5046. PMID: 29727562: PMCID: PMC6540792

4. My laboratory has more recently studied the connection between metabolism with cancer signaling and chromatin regulation, with a particular focus on the acetyl-CoA metabolism and metabolite acylation enzymes such as ATP citrate lyase (ACLY). Our studies uncovered the molecular mechanism of ACLY and provided a molecular scaffold for the structure-based development of ACLY inhibitors for therapy of cancer and metabolic and cardiovascular disorders.
a. Bazilevsky, G.A., Affronti, H.C., Wei, X., Campbell, S.L., Wellen, K.E. and Marmorstein. R. ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis, (2019) J. Biol. Chem. 294:7529-7268. PMID: 30877197; PMCID: PMC6509486
b. Wei, X., Schultz, K., Bazilevsky, G.A., Vogt, A. and Marmorstein R. Molecular basis of acetyl-CoA production by ATP-citrate lyase. (2020) Nature Structural & Molecular Biology 27:33-41. PMID: 31873304
Wei, X. and Marmorstein, R., Reply to: Acetyl-CoA is produced by the citrate synthetase homology module of ATP-citrate lyase. (2021) Nat. Struct. Mol. Biol., 28: 639-641. PMID34294921
Wei, X., Kixmoeller, K., Baltrusaitis, E., Yang, X. and Marmorstein, R. Allosteric role of a structural NADP+ molecule in glucose-6-phosphate dehydrogenase activity, (2022) Proc. Nat. Acad. Sci. USA, 119(29): e2119695119

Research Interest

The Marmorstein laboratory studies the molecular mechanisms of (1) epigenetic regulation (2) protein post- and co-translational modification with a particular focus on protein acetylation, and (3) enzyme signaling in cancer and metabolism. The laboratory uses a broad range of biochemical, biophysical and structural research tools (X-ray crystallography and cryo-EM) to determine macromolecular structure and mechanism of action. The laboratory also uses high-throughput small molecule screening and structure-based design strategies to develop protein-specific small-molecule probes to interrogate protein function and for preclinical studies.

Jennifer E. Phillips-Cremins, Ph.D.

Contributions to Science

The Cremins Lab focuses on higher-order genome folding and how chromatin works through long-range, spatial mechanisms to govern neural specification and synaptic plasticity in healthy and diseased neural circuits. We have developed molecular and computational technologies to create kilobase-resolution maps of chromatin folding and have built synthetic architectural proteins to engineer loops with light, together catalyzing new understanding of the genome’s structure-function relationship. We applied our technologies to discover that topologically associating domains (TADs), nested subTADs, and loops undergo marked reconfiguration during neural lineage commitment, somatic cell reprogramming, neuronal activity stimulation, and in models of repeat expansion disorders. We have demonstrated that loops induced by neural circuit activation, engineered through synthetic architectural proteins, and miswired in fragile X syndrome (FXS) are tightly connected to transcription, thus providing early insight into the genome’s structure-function relationship. Moreover, we have also demonstrated that cohesin-mediated loop extrusion can position the location of human replication origins which fire in early S phase, revealing a role for genome structure beyond gene expression in DNA replication. Recently, we have discovered that nearly all unstable short tandem repeat tracts in trinucleotide expansion disorders are localized to the boundaries between TADs, suggesting they are hotspots for pathological instability. We have identified that Mb-scale H3K9me3 domains decorating autosomes and the X chromosome in FXS are exquisitely sensitive to the length of the CGG STR tract. H3K9me3 domains spatially connect via inter-chromosomal interactions to silence synaptic genes and stabilize STRs prone to instability on autosomes. Together, our work uncovers a link between subMegabase-scale genome folding and genome function in the mammalian brain, thus providing the foundation upon which we will dissect the functional role for chromatin mechanisms in governing defects in synaptic plasticity and long-term memory in currently intractable and poorly understood neurological disorders.

Research Interest

The Cremins lab aims to understand how chromatin works through long-range physical folding mechanisms to encode neuronal specification and long-term synaptic plasticity in healthy and diseased neural circuits. We pursue a multi-disciplinary approach integrating data across biological scales in the brain, including molecular Chromosome-Conformation-Capture sequencing technologies, single-cell imaging, optogenetics, genome engineering, induced pluripotent stem cell differentiation to neurons/organoids, and in vitro and in vivo electrophysiological measurements.

Our long-term scientific goal is to dissect the fundamental mechanisms by which chromatin architecture causally governs genome function and, ultimately, long-term synaptic plasticity and neural circuit features in healthy mammalian brains as well as during the onset and progression of neurodegenerative and neurodevelopmental disease states

Our long-term mentorship goal is to develop a diverse cohort of next-generation scientific thinkers and leaders cross-trained in molecular and computational approaches. We seek to create a positive, high-energy environment with open and honest communication to empower individuals to discover and refine their purpose and grow into the best versions of themselves.

Arjun-Raj

Arjun Raj, Ph.D.

Contribution to Science

We have contributed to the understanding of mechanisms that create and control cell-to-cell variability in gene expression. In particular, our work was amongst the first to use quantitative single molecule RNA detection techniques to describe the phenomenon of transcriptional bursts, in which we found that transcription is a pulsatile process consisting of pulses of activity interspersed with periods when the gene is completely inactive (Raj et al. PLOS Bio 2006, Leveque and Raj Nat Meth 2013a). We also contributed to the mathematical modeling of this field (Raj et al. PLOS Bio 2006). We have now shown how these pulses relate to homeostatic mechanisms that maintain transcript concentration despite changes in cell volume and DNA content (Padovan-Merhar et al. Mol Cell 2015). We have also shown that variability can be used as a tool for dissecting mechanisms of transcriptional control of molecules such as long non-coding RNA (Maamar et al. Genes and Dev. 2013).

Raj A, Peskin CS, Tranchina D, Vargas DY, Tyagi S. Stochastic mRNA synthesis in mammalian cells.PLoS Biol. 2006 Oct;4(10):e309. PubMed PMID: 17048983; PubMed Central PMCID: PMC1563489.
Levesque MJ, Raj A. Single-chromosome transcriptional profiling reveals chromosomal gene expression regulation. Nat Methods. 2013 Mar;10(3):246-8. doi: 10.1038/nmeth.2372. Epub 2013 Feb 17. Erratum in: Nat Methods. 2013 May;10(5):445. PubMed PMID: 23416756; PubMed Central PMCID: PMC4131260.
Maamar H, Cabili MN, Rinn J, Raj A. linc-HOXA1 is a noncoding RNA that represses Hoxa1 transcription in cis. Genes Dev. 2013 Jun 1;27(11):1260-71. doi: 10.1101/gad.217018.113. Epub 2013 May 30. PubMed PMID: 23723417; PubMed Central PMCID: PMC3690399.
Padovan-Merhar O, Nair GP, Biaesch AG, Mayer A, Scarfone S, Foley SW, Wu AR, Churchman LS, Singh A, Raj A. Single Mammalian Cells Compensate for Differences in Cellular Volume and DNA Copy Number through Independent Global Transcriptional Mechanisms. Mol Cell. 2015 Apr 16;58(2):339-52. doi: 10.1016/j.molcel.2015.03.005. Epub 2015 Apr 9. PubMed PMID: 25866248; PubMed Central PMCID: PMC4402149.

We have contributed to the understanding of how cell-to-cell variability can lead to phenotypic consequences. Specifically, we showed that variability in transcription can lead to random cell fate decisions in bacteria (Maamar and Raj et al. Science 2008), and that variability in gene expression can lead to phenotypic variability in metazoan development (Raj and Rifkin et al. Nature 2010). More recently, we have linked gene expression variability to single cell non-genetic resistance mechanisms in melanoma (Shaffer et al. Nature, in press).

Maamar H, Raj A, Dubnau D. Noise in gene expression determines cell fate in Bacillus subtilis. Science. 2007 Jul 27;317(5837):526-9. Epub 2007 Jun 14. PubMed PMID: 17569828; PubMed Central PMCID: PMC3828679.
Raj A, Rifkin SA, Andersen E, van Oudenaarden A. Variability in gene expression underlies incomplete penetrance. Nature. 2010 Feb 18;463(7283):913-8. doi: 10.1038/nature08781. PubMed PMID: 20164922; PubMed Central PMCID: PMC2836165.
Shaffer SM, Dunagin M, Torborg S, Torre EA, Emert T, Krepler C, Beqiri M, Sproesser K, Brafford P, Xiao M, Eggan E, Anastopoulos IN, Vargas-Garcia CA, Singh A, Nathanson K, Heryn M, Raj A. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature, in press.

We have contributed to methodological approaches to measuring expression and transcription in single cells via RNA fluorescence in situ hybridization (RNA FISH). First, we developed a method that greatly simplifies the detection of individual RNA molecules by RNA FISH (Raj et al. Nat Meth 2008). We have since pushed the method to high multiplexing in the detection of chromosome structure and gene expression simultaneously (Levesque and Raj, Nat Meth 2013a). We also have enabled the detection of single nucleotide variants on individual RNA molecules (Levesque et al. Nat Meth 2013b), which allows for mutation detection and measurements of allele-specific expression. Further, we have developed an ultra-fast variant of RNA FISH that enables use in diagnostic and point of care settings (Shaffer et al. PLOS ONE 2013).

Raj A, van den Bogaard P, Rifkin SA, van Oudenaarden A, Tyagi S. Imaging individual mRNA molecules using multiple singly labeled probes. Nat Methods. 2008 Oct;5(10):877-9. doi: 10.1038/nmeth.1253. Epub 2008 Sep 21. PubMed PMID: 18806792; PubMed Central PMCID: PMC3126653.
Levesque MJ, Raj A. Single-chromosome transcriptional profiling reveals chromosomal gene expression regulation. Nat Methods. 2013 Mar;10(3):246-8. doi: 10.1038/nmeth.2372. Epub 2013 Feb 17. Erratum in: Nat Methods. 2013 May;10(5):445. PubMed PMID: 23416756; PubMed Central PMCID: PMC4131260.
Levesque MJ, Ginart P, Wei Y, Raj A. Visualizing SNVs to quantify allele-specific expression in single cells. Nat Methods. 2013 Sep;10(9):865-7. doi: 10.1038/nmeth.2589. Epub 2013 Aug 4. PubMed PMID: 23913259; PubMed Central PMCID: PMC3771873.
Shaffer SM, Wu MT, Levesque MJ, Raj A. Turbo FISH: a method for rapid single molecule RNA FISH. PLoS One. 2013 Sep 16;8(9):e75120. doi: 10.1371/journal.pone.0075120. eCollection 2013. PubMed PMID: 24066168; PubMed Central PMCID: PMC3774626.

Research Interest

Our lab aims to develop a quantitative understanding of the molecular biology of the cell. Interests include chromosome structure and gene expression, non-coding RNA, and global regulation of gene expression. Applications include genetics, cancer and stem cells.

Junwei Shi, Ph.D.

Contributions to Science

Contributions to Science

  1. Identifying Epigenetic Dependencies in Leukemia.
  2. CRISPR-based Genetic Screening Methods
  3. Identifying Transcriptional, Epi-transcriptional and Kinase Dependencies in Leukemia.
  4. Investigating Genetic Regulatory Pathways using CRISPR-based Screening Methods.

Research Interest

The physiological effects of cancer are a manifestation of the genetic abnormalities that cause the disease. While much progress has been made in the understanding of such genetic perturbations, scientists still struggle to effectively identify, understand, and treat cancer-causing mutations. This is due to the fast-paced evolution of the disease, and the accumulation of novel mutations that permit cell survival even in the harsh environment created by a therapeutic. CRISPR is a gene-editing technology that couples the elegance of base complementarity with the enzymatic activity of a DNA nuclease in order to introduce mutations into target loci. CRISPR technologies help advance our understanding of the genetic perturbations that contribute to cancer maintenance.

Doris Wagner, Ph.D.

Contribution to Science

Topics of study
The role and Regulation of SWI/SNF chromatin remodeling complexes in plants.
ATP-dependent chromatin remodeling can change the chromatin state by using the energy derived from ATP hydrolysis to alter histone/DNA interactions. We uncovered key roles for plant SWI/SNF subfamily remodelers in stem cell maintenance and in overcoming Polycomb repression for induction of the floral homeotic genes during flower patterning. Finally, activity of one of the SWI/SNF remodelers, BRM, is modulated directly by signaling components of the stress hormone ABA for drought tolerance.
Kwon, C.S., Chen, C., and Wagner, D. (2005). WUSCHEL is a primary target for transcriptional regulation by SPLAYED in dynamic control of stem cell fate in Arabidopsis. Genes Development 19, 992-1003.
Bezhani, S., Winter, C., Hershman, S., Wagner, J.D., Kennedy, J.F., Kwon, C.S., Pfluger, J., Su, Y., and Wagner, D. (2007). Unique, Shared, and Redundant Roles for the Arabidopsis SWI/SNF Chromatin Remodeling ATPases BRAHMA and SPLAYED. Plant Cell 19, 403-416.
Han, S.K., Sang, Y., Rodrigues, A., BIOL425F2010, B., Rodriquez, P.L. and Wagner, D. (2012) The SWI2/SNF2 chromatin remodeling ATPase BRAHMA represses Abscisic Acid Responses in the Absence of the Stress Stimulus in Arabidopsis, Plant Cell 24 4892-4906.
Wu, M.F., Sang, Y., Bezhani, S., Yamaguchi, N., Han, S.K., Li, Z., Su, Y., Slewinski, T.L., and Wagner, D. (2012). SWI2/SNF2 chromatin remodeling ATPases overcome polycomb repression and control floral organ identity with the LEAFY and SEPALLATA3 transcription factors. Proceedings of the National Academy of Sciences of the United States of America 109, 3576-3581. http://www.eurekalert.org/pub_releases/2015-10/uop-ph101315.php
Peirats-Llobet, M., Han, S.K., Gonzalez-Guzman, M., Jeong, C.W., Rodriguez, L., Belda-Palazon, B., Wagner, D*., and Rodriguez, P.L*. (2016). A Direct Link between Abscisic Acid Sensing and the Chromatin-Remodeling ATPase BRAHMA via Core ABA Signaling Pathway Components. Molecular Plant 9, 136-147. * corresponding authors
The switch to flower formation, a major developmental switch critical for reproductive success.
Plants generate different types of lateral organs (leaves, then branches and finally flowers) post-embryonically from stem cell descendants at the shoot apex. When flowers form is critical for plant reproductive success. Our research has established that the plant specific helix-turn-helix transcription factor LEAFY is a key regulator of the onset of flower formation. We showed that the regulatory network downstream of LFY is comprised of a set of interlocking feed-forward loops that together control the timing of the upregulation of the direct LFY target APETALA1, a commitment factor of floral fate. We further found that LFY directly alters the hormone environment in newly formed primordia to promote floral fate.
Yamaguchi, A., Wu, M.F., Yang, L., Wu, G., Poethig, R.S., and Wagner, D. (2009). The microRNA-regulated SBP-Box transcription factor SPL3 is a direct upstream activator of LEAFY, FRUITFULL, and APETALA1. Developmental Cell 17, 268-278. (faculty 1000 recommended)
Winter, C.M., Austin, R.S., Blanvillain-Baufume, S., Reback, M.A., Monniaux, M., Wu, M.F., Sang, Y., Yamaguchi, A., Yamaguchi, N., Parker, J.E., J.E., Parcy, F., Jensen, S.T., Li, H., Wagner, D. (2011). LEAFY Target Genes Reveal Floral Regulatory Logic, cis Motifs, and a Link to Biotic Stimulus Response. Developmental Cell 20, 430-443.
Yamaguchi, N., Winter, C., Wu, M-F., Kanno, Y., Yamaguchi, A., Seo, M., and Wagner, D. (2014) Gibberellin acts positively then negatively to control onset of flower formation in Arabidopsis. Science 344, 638-41. https://stke.sciencemag.org/content/7/325/ec127); http://www.eurekalert.org/pub_releases/2014-05/uop-phh050814.php
Zhu, Y., Klasfeld, S., Jeong, C.W., Jin, R., Goto, K., Yamaguchi, N., and Wagner, D. TERMINAL FLOWER 1-FD complex target genes and competition with FLOWERING LOCUS T. Nature Communications, 11, 5118. https://www.eurekalert.org/pub_releases/2020-10/uop-dpg100920.php
Jin, R., Klasfeld, S., Garcia, M.F., Xiao, J., Han, S.K., Konkol, A., Zhu, Y., and Wagner, D.. LEAFY is a pioneer transcription factor and licenses cell reprogramming to floral fate. 2021  Nature Communications, 12(1):626. https://www.eurekalert.org/pub_releases/2021-01/uop-fe012721.php
Organogenesis and differentiation in response to hormonal cues
We have recently become interested in the question how hormone responses control organogenesis and differentiation. We have identified key targets of a master transcriptional regulator of the auxin hormone response, AUXIN RESPONSE FACTOR5/MONOPTEROS during organogenesis (flower primordium initiation) and uncovered an auxin hormone triggered chromatin state switch. In addition, we have elucidated how BRM together with leaf maturation transcription factors triggers leaf differentiation by lowering response to the hormone cytokinin.
Yamaguchi, N., Wu, M.-F., Winter, C., Berns, M., Nole-Wilson, S., Yamaguchi, A., Coupland, G., Krizek, B., and Wagner, D. (2013) Auxin-mediated Initiation of the Flower Primordium. Developmental Cell 24, 1–12. (faculty 1000 recommended)
Efroni, I., Han, S.K., Kim, H.Y., Wu, M.F., Sang, Y., Hong, J.C., Eshed, Y*., and Wagner, D*. (2013). Regulation of leaf maturation by chromatin-mediated modulation of hormonal responses. Developmental Cell. 24, 438-445. *corresponding authors
Wu, M-F, Yamaguchi, N., Xiao J., Bargmann, B. Estelle, M., Sang, Y. and Wagner, D. (2015) Auxin-regulated chromatin switch directs acquisition of flower primordium founder fate. eLife;4:e09269 http://www.eurekalert.org/pub_releases/2015-10/uop-ph101315.php
Chung, Y., Zhu, Y., Wu,M.-F., Simonini, S., Armenta-Medina, A.,  Jin, R.,  Østergaard, L.,  Gillmor, C.S., and Wagner, D. (2019) Auxin Response factors promote organogenesis by chromatin-mediated repression of the pluripotency gene SHOOTMERISTEMLESS. Nature Communications 10, 886.
Polycomb silencing and recruitment in plants
Cell identity depends on silencing of unnecessary or detrimental gene expression programs. To understand the regulation of epigenetic gene silencing we have elucidated how Polycomb Repressive Complexes are targeted to developmental genes in plants. We have uncovered a genome-encoded recruitment mechanism very similar to that previously described in the fruitfly. Our studies pave the way to future epigenetic manipulation of desirable plant traits.
Bossi, F., Fan, J., Xiao, J., Chandra, L., Shen, M., Dorone, Y., Wagner, D., and Rhee, S.Y. (2017). Systematic discovery of novel eukaryotic transcriptional regulators using sequence homology independent prediction. BMC Genomics 18, 480.
Xiao, J., Jin, R., Yu, X., Shen, M., Wagner, J.D., Pai, A., Song, C., Zhuang, M., Klasfeld, S., He, C., Santos, A. M., Helliwell, C., Pruneda-Paz, J. L., Kay, S. A., Lin, X., Cui, S., Garcia, M. F., Clarenz, O., Goodrich, J., Zhang, X., Austin, R. S., Bonasio, R., Wagner, D. (2017). Cis and trans determinants of epigenetic silencing by Polycomb repressive complex 2 in Arabidopsis. Nat Genet. 49 (10) 1546-1552  preview in NG. https://www.eurekalert.org/pub_releases/2017-08/uop-pbs082117.php
Sun, B., Zhou, Y., Cai, J., Shang, E., Yamaguchi, N., Xiao, J., Looi, L.S., Wee, W.Y., Gao, X., Wagner, D. and Ito, T. (2019). Integration of transcriptional repression and Polycomb-mediated silencing of WUSCHEL in floral meristems. Plant Cell.
Bieluszewski, T., Xiao, J., Yang, Y., and Wagner, D. (2021). PRC2 activity, recruitment, and silencing: a comparative perspective. Trends Plant Sci 26, 1186-1198.
Lee, U.S., Bieluszewski, T., Xiao, J., Yamaguchi, A., and Wagner, D. (2022). H2A.Z contributes to trithorax activity at the AGAMOUS locus. Mol Plant 15, 207-210.

Research Interest

(Re)programming Cell Identity and Function in the Context of Chromatin

Our research focuses on the reprogramming of cell identity and function during developmental transitions and in response to environmental inputs in plants. Reprogramming offers a window of opportunity to unravel the regulatory logic that underlies cell fate and function as existing programs are shut down and new one’s are put in place. Plants are an excellent experimental system to address this question as they tailor their final form and cell function to a changing environment to optimize growth and survival. We have shown that master transcriptional regulators, hormone response and chromatin state together orchestrate cell fate reprogramming in plants.

Shelley L. Berger, Ph.D.

Contributions to Science

1.  Identification of transcriptional adaptors/coactivators Gcn5/Ada2/Ada3 and discovery of novel histone modifications and mechanisms in transcription and sperm genome opening

We discovered transcriptional “adaptors”, which we showed associate with DNA binding activators, a groundbreaking new model for transcriptional activation, to reveal how histone enzymatic modifiers are recruited to genes (Berger+, Cell1990, Cell1993). We revealed the importance of adaptor Gcn5 acetyltransferase activity in transcriptional activation (1998), unifying transcription and chromatin regulation. We discovered numerous novel histone modifications (PTMs), PTM cross-talk, and sequential histone PTMs in transcription, including histone phosphorylation/acetylation (2001) and ubiquitylation/deubiquitylation. We discovered (2017) that enhancer RNAs bind directly to CBP, the key metazoan acetyltransferase, to stimulate HAT activity in vitro and at enhancers in vivo.  We showed (2019) that Gcn5 provides key histone acetylation to broadly open the mouse genome during spermatogenesis for extensive chromatin restructuring.

a.  Wang L, Liu L. and Berger SL. (1998) Critical residues for histone acetylation by GCN5, functioning in Ada and SAGA complexes, are also required for transcriptional function in vivo. Genes & Development 12: 640-653. PMCID: PMC316586

b.  Lo W-S…Shiekhattar R, and Berger SL.  (2001) Snf1 is a histone kinase which works in concert with the histone acetyltransferase Gcn5 to regulate transcription. Science 293:1142-6.  PMID:111498592

c.  Bose DA, Donahue G, Reinberg D, Shiekhattar R, Bonasio R, Berger SL. (2017)  RNA binding to CBP stimulates histone acetylation and transcription. Cell 168,135-149. PMCID: PMC5325706.

d.  Luense LJ, Donahue G, Lin-Shiao E….Bartolomei M, Berger SL. (2019) Gcn5-mediated histone acetylation governs nucleosome dynamics in spermiogenesis. Developmental Cell 51:745-758.

2. Discovery of chromatin mechanisms controlling aging and senescence

We uncovered chromatin changes involved in aging and cellular senescence, indicating broad epigenome dysregulation. These include pioneering studies that histone acetylation drives aging in yeast (2009), disrupts the nuclear laminar chromatin in mammals, and are crucial to enhancer function in aging (2019). We showed these disruptions trigger both homeostatic genomic protection and cellular damage, and discovered nuclear autophagy pathways in senescence leading to inflammation in aging and cancer (2015,2017,2020). Our findings suggest potential epigenetic therapeutics to ameliorate age-associated disease.

a.  Dang W…Kaeberlein M, Kennedy BK, and Berger SL. (2009) Histone H4 lysine-16 acetylation regulates cellular lifespan. Nature 459:802-7. PMCID: PMC2702157.

b.  Dou Z…Adams PD^, and Berger SL^. (2015) Autophagy mediates degradation of nuclear lamina. Nature 527:105-9. PMCID: PMC4824414.   (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:402-406.  PMID:28976970.

c.  Sen P, Lan Y…Adams PD, Schultz DC, Berger SL. (2019) Histone acetyltransferase p300 induces de novo super-enhancers to drive cellular senescence. Molecular Cell 73:684-698. PMID:30773298.

d.  Xu C, Wang L…Adams PA, Ott M, Tong W, Johansen T, Dou Z^, and Berger SL^.  (2020)  SIRT1 is downregulated by autophagy in senescence and aging.  Nature Cell Biology 22:1170-1179.

3. Demonstration of chromatin mechanisms controlling memory and behavior and relevant to aging. 

Our studies in mouse brain and memory show a pivotal role of the metabolic enzyme, ACSS2, in fueling “on-site” acetyl-CoA generation on chromatin for neuronal histone acetylation and gene expression in normal memory and in alcohol-fueled addiction memory (2017/19). Our work in human Alzheimer’s disease reveals that the cognitively normal aging brain is epigenetically protected compared to the AD brain (2018/20). In other research on brain, we pioneered investigation of eusocial ant caste-specific behavior for organismal-level chromatin regulation and epigenetics, owing to the remarkable fact that female ants of distinct social castes (such as queen, soldier, and forager) share an identical genome. We sequenced the first ant genomes and then profiled the first histone modification epigenomes (2010,Science) and pioneered Crispr genetics in ants (2017,Cell). Groundbreaking results indicate a critical role of histone modifications in altering ant brain function to instruct complex social behavior; we identified a “window”, early after hatching, to behavioral reprogramming via epigenetic manipulation (2016/2020).  We linked regulation of caste behavior to remarkable aging disparity.

a.  Simola DF…Reinberg D^, Liebig J^, Berger SL^.  (2016)  Epigenetic (re)programming of caste-specific behavior in the ant C. floridanus. Science 351:aac6633. PMID: 26722000, PMCID: PMC5057185.

b.  Mews, P… Berger SL. (2017) Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and hippocampal memory. Nature 546,381-386. PMCID: PMC5505514.  Mews P, Egervari G^…Garcia, B, Berger SL^. (2019) Alcohol metabolism contributes to brain histone acetylation. Nature 574: 717-721.

c.  Glastad K, Graham RJ, Ju L, Rossler J, Brady CM, and Berger SL (2020) Epigenetic regulator CoRest controls social behavior in ants.  Molecular Cell 77:338-351.

d.  Nativio R, Donahue G…Johnson FB^, Bonini NM^, Berger SL^ (2018) Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nature Neuroscience 21,497-505.  Nativio R, Lan Y…Garcia BA, Trojanowski JQ, Bonini NM^, Berger SL^.  (2020) An integrated multi-omics approach identifies epigenetic drivers associated with Alzheimer’s disease.  Nature Genetics 52:1024-1035.

  1. Discovery of tumor suppressor p53 factor and histone modifications and their mechanisms including activating p53 acetylation, repressive p53 methylation, and novel chromatin pathways in p53-mediated transcriptional activation

Our work revealed new enzyme modifiers and post-translational modifications of p53 (including acetylation, methylation, and demethylation, 2006/7) regulating p53 activity. Our findings propelled broad efforts in the field to discover novel acetylation and methylation of transcription factors. We showed p53 methylation is generally repressive to its function, and showed repressive p53 methylation occurring in certain cancers bearing high levels of wild type p53. We discovered novel epigenetic pathways used by wild type and mutant p53 in regulating chromatin structure/function in normal and cancer cells, such as gain-of-function p53 mutants driving transcriptional activating and growth promoting histone modifications (2015).  We showed that p53 and p63 establish new enhancers during stress and development. We found a novel role of p53 in promoting target gene association with nuclear speckles for transcriptional amplification (2021).

  1. a. Huang J…Jenuwein T, andBerger SL. (2006) Repression of p53 activity by Smyd2-mediated methylation.  Nature 444:629-32. PMID:17108971.  Huang J…Jenuwein T, and Berger SL.  (2007) p53 is regulated by the lysine demethylase LSD1.  Nature, 449:105-8.
  2. Bungard D…Thompson CB, Jones RG andBerger SL. (2010) Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329: 1201-5. PMCID: PMC3922052.
  3. Zhu J, Sammons MA, Donahue G, Dou Z…Arrowsmith CH, andBerger SL. (2015) Gain-of-function p53 mutants co-opt epigenetic pathways to drive cancer growth. Nature 525:206-11. PMCID: PMC4568559
  4. Alexander KA…Belmont A, Joyce EF, Raj A, and Berger SL. (2021) p53 mediates target gene association with nuclear speckles for amplified RNA expression. Molecular Cell 81:1666-1681.
  1. Investigation of epigenetic mechanisms in T and CART cell exhaustion and cancer immunotherapy

We established collaborations with Carl June (pioneer of CAR T cell therapy in cancer) and John Wherry (discovered key aspects of T cell exhaustion).  We investigate epigenetic regulation in patient response to immunotherapy, and controlling T cell exhaustion in mouse models.

  1. Pauken KE…Berger SL, and Wherry EJ.  (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.Science 354,1160-1165.  Khan O…Berger SL, and Wherry EJ.  (2019) TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion.  Nature 571, 211.
  2. Fraietta JA…Berger SL, Bushman FD, June CH, and Melenhorst JJ. (2018) Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T-cells.Nature 555, 307-312.
  3. Chen Z…Berger SL, Wherry EJ, and Shi J.  In vivo CRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer.  Cell 184:1262.
  4. Good CR+, Kuramitsu S+, Aznar MA+…Young RM^,Berger SL^, June CH^ (2021) In vitro dysfunction model reveals the plasticity of patient CAR-T cells and identifies transcription factors whose modulation can restrain CAR-T cell exhaustion. Cell, 184:6081-6100.

Research Interest

Our lab focuses on mechanisms that regulate gene expression with a special emphasis on how the DNA-packaging structure of chromatin is manipulated during genomic processes. Our findings inform the study of cancer and other diseases, and ultimately drug discovery.

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