Kavitha Sarma, Ph.D.

R-loop biology.
R-loops are RNA containing chromatin structures that have the potential to be powerful regulators of epigenetic gene expression. Many questions about where R-loops form, what protein factors function to modulate these structures in vivo, and their mechanisms in gene regulation remain unanswered. As an independent investigator, I drew on my considerable expertise in protein and RNA biochemistry to initiate projects to understand the function and mechanisms of R-loops. We developed a novel technique that we named, “MapR”, that combines the specificity of RNase H for DNA:RNA hybrids with the sensitivity, speed, and convenience of the CUT&RUN approach, whereby targeted genomic regions are released from the nucleus by micrococcal nuclease (MNase) and sequenced directly, without the need for affinity purification. MapR is an antibody independent, recombinant protein-based technology that is fast, sensitive, and easy to implement (Yan et al, 2019). Also, we have recently improved MapR to increase resolution and confer strand specificity (Wulfridge and Sarma, 2021) and have used proximity proteomics to identify the R-loop proteome (Yan et al, 2022). We discovered a previously unappreciated role for zinc finger and homeodomain proteins in R-loop regulation and identified ADNP, a high confidence autism spectrum disorder gene, as an R-loop resolver.

Yan Q*, Shields, EJ*, Bonasio R†, Sarma K†. 2019. Mapping native R-loops genome-wide using a targeted nuclease approach. Cell Rep, 29(5):1369-1380. PMC6870988.
Yan Q, Sarma K. 2020. MapR: A method for identifying native R-loops genome-wide. Curr Protoc Mol Biol. 130(1):e113. PMC6986773.
Wulfridge P, and Sarma K. 2021. A nuclease- and bisulfite-based strategy captures strand-specific R-loops genome-wide. eLife 10:e65146. PMC7901872.
Yan Q*, Wulfridge P*, Doherty J, Fernandez-Luna JL, Real PJ, Tang HY, Sarma K. 2021. Proximity labeling identifies a repertoire of site-specific R-loop modulators. Nature Commun. 13(1):53. PMCID: PMC8748879. ‘*’- equal contribution.

Non-coding RNA regulation.
As a post-doctoral fellow, I applied my expertise in biochemistry to investigate the significance of interactions between proteins and long non-coding RNAs (lncRNAs) in the context of X chromosome inactivation. I discovered a novel use for locked nucleic acids (LNAs) in the study of lncRNA function. The mechanism of Xist RNA spreading had remained an open question in the field since its discovery in the 1990s. Using LNAs, I found that Xist RNA utilizes both repetitive and unique elements within itself to spread uniformly over the entire X chromosome to silence it (Sarma et al, 2010). Furthermore, combining the use of LNAs with a high throughput sequencing approach (CHART) allowed us to identify regions of the genome that were bound by Xist RNA (Simon et al, 2013). The use of LNAs was key in discovering that Xist RNA utilizes distinct mechanisms to coat the inactive X chromosome at different developmental stages. This technology has been patented and commercialized and is now being used to functionally characterize several different non-coding RNAs that play important roles in cellular homeostasis. During this time, I also contributed to examining the interactions between the PRC2 complex and Xist RNA (Cifuentes-Rojas et al, 2014), and discovered ATRX to be a high affinity RNA binding protein that interacts with Xist RNA to regulate PRC2 enrichment on the inactive X chromosome (Sarma et al, 2014).

Sarma K, Levasseur P, Aristarkhov A, Lee JT. 2010. Locked nucleic acids (LNAs) reveal sequence requirements and kinetics of Xist RNA localization to the X chromosome. Proc Natl Acad Sci U S A 107:22196-22201. PMCID: PMC3009817.
Simon MD*, Pinter SF*, Fang R*, Sarma K, Rutenberg-Schoenberg M, Bowman SK, Kesner BA, Maier VK, Kingston RE, Lee JT. 2013. High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature 504:465-469. PMCID: PMC3904790.
Cifuentes-Rojas C, Hernandez AJ, Sarma K, Lee JT. 2014. Regulatory interactions between RNA and polycomb repressive complex 2. Mol Cell 55:171-185. PMCID: PMC4107928.
Sarma K, Cifuentes-Rojas C, Ergun A, Del Rosario A, Jeon Y, White F, Sadreyev R, Lee JT. 2014. ATRX regulates binding of PRC2 to Xist RNA and Polycomb targets. Cell 159:1228. PMID: 28898627.

Histone methyltransferases and Polycomb proteins.
I have spent a large part of my career working toward understanding the role of various chromatin factors in epigenetic gene regulation. As a graduate student, I purified and characterized some of the first reported histone lysine methyltransferases (HKMTs) such as PR-Set7, Set9, and the Polycomb Repressive Complex 2 (PRC2). During this time, I also developed and characterized reagents and tools that were critical to advance research in this field. My discovery that the mammalian homolog of the drosophila polycomblike protein (PHF1), a PRC2 accessory factor, facilitates the activity of the PRC2 complex provided first evidence of the role of accessory proteins in the function of the PRC2 complex (Sarma et al, 2008). Recent publications by several independent groups underscore the importance of PHF1 and other polycomblike proteins in PRC2 function. As a post-doctoral fellow, I discovered that the chromatin remodeler ATRX regulates PRC2 localization genome-wide (Sarma et al, 2014). In my own lab, we showed that ATRX-RNA interactions specify PRC2 targeting to a subset of polycomb targets (Ren et al, 2020). We also discovered that ATRX mutations in the histone binding or the helicase domains have distinct effects on PRC2 localization and neuronal differentiation (Bieluszewska et al, 2022).

Sarma K, Margueron R, Ivanov A, Pirrotta V, Reinberg D. 2008. Ezh2 requires PHF1 to efficiently catalyze H3 lysine 27 trimethylation in vivo. Mol Cell Biol 28:2718-2731. PMCID: PMC2293112.
Sarma K, Cifuentes-Rojas C, Ergun A, Del Rosario A, Jeon Y, White F, Sadreyev R, Lee JT. 2014. ATRX regulates binding of PRC2 to Xist RNA and Polycomb targets. Cell 159:1228. PMID: 28898627.
Ren W*, Medeiros N*, Warneford-Thomson R, Wulfridge P, Yan Q, Bian J, Sidoli S, Garcia BA, Skordalakes E, Joyce E, Bonasio R, Sarma K. 2020. Disruption of ATRX-RNA interactions uncovers roles in ATRX localization and PRC2 function. Nat Commun. 6;11(1):2219. PMID: 32376827
Bieluszewska A, Wulfridge P, Doherty J, Ren W, Sarma K. (2022). ATRX histone binding and helicase activities have distinct roles in neuronal differentiation. Nucleic Acids Res. PMC in progress

Research Interest

The Sarma lab focuses on elucidating the molecular mechanisms of RNA mediated epigenetic gene regulation in eukaryotes. Using various cell culture models including mouse embryonic stem cells, neuronal differentiation systems, and cancer models, we employ biochemical and various -omics tools to examine the mechanisms of RNAs and their interactions with chromatin and epigenetic modifiers in gene regulation. We have become increasingly interested in RNA containing chromatin structures called R-loops and how they are misregulated in neurodevelopmental disorders and cancers and their impact on genomic processes that can drive disease. Most recently, we developed high throughput sequencing methods to profile native R-loops and identified R-loop interactors using a proximal proteomic approach.

Montserrat Anguera, Ph.D.

1. Functional characterization of long noncoding RNAs that regulate gene expression during development and in adulthood. As a postdoctoral fellow, I began investigating epigenetic mechanisms and modeling these mechanisms of gene expression using conditional knockout mouse models. I demonstrated that the Tsx gene does not encode for a protein but instead is transcribed as a long noncoding RNA, similar to other neighboring genes. I generated a conditional knockout mouse for Tsx and discovered that Tsx RNA has functions beyond the germline, affecting stem cell growth, expression of neighboring genes that regulate X-chromosome inactivation, and also behavior in a gender-specific fashion. This work provided a conceptual foundation for experimentally testing for coding potential of noncoding RNAs and for their functional characterization. As an associate professor, my lab continues to study epigenetic mechanisms of gene expression involving long noncoding RNAs from the X chromosome. We have also investigated sex-specific gene expression profiles during human placental development using in vitro pluripotent stem cell derived model systems. In addition, my lab continues to have a long-standing interest in functional characterization of novel X-linked long noncoding RNAs. We discovered LNCRHOXF1 which functions during early placental development.

  • Anguera, M.C., Ma, W., Clift, D., Namekawa, S., Kelleher, R.J, and Lee, J.T. (2011). “Tsx produces a long noncoding RNA and has general functions in the germline, stem cells, and brain.” PLoS Genet. 7 (9):1-14. PMCID: PMC3164691
  • Ian Penkala, Camille Syrett, Jianle Wang, and Montserrat C. Anguera. (2016). “LNCRHOXF1: a long noncoding RNA from the X-chromosome that suppresses viral response genes during development of the early human placenta”. Mol Cell Biol. Apr 11, 2016, PMID: 27066803
  • Camille Syrett, Isabel Sierra, Corbett Berry, Daniel Beiting, and Montserrat C. Anguera. (2018) “Sex-specific gene expression during differentiation of human pluripotent stem cells to trophoblast progenitors”. Stem Cells Dev. July 11; PMID: 29993333

2. Defining abnormal X-Chromosome Inactivation maintenance in human pluripotent stem cells. During my postdoc, I also investigated human X-Chromosome Inactivation (XCI) in the pluripotent state to specifically determine whether reprogramming human female fibroblasts would reactive the inactive X chromosome. I discovered that the reprogramming process generated a heterogeneous mixture of X-Inactivation cells, distinguishable by their expression pattern for the long noncoding RNA XIST. I made the critical observation that loss of XIST RNA expression in human pluripotent stem cells results in the acquisition of cancer-like phenotypes. This work was the first to demonstrate that human female pluripotent stem cells are potentially dangerous in a clinical setting. These experiments are the basis for my current research program investigating how abnormal expression from the inactive X, resulting from aberrant XCI maintenance, is involved in female-biased autoimmunity, where X-silencing is compromised.

  • Anguera, M.C., Sadreyev, R., Zhang, Z., Szanto, A., Sheridan, S., Haggerty, S., Jaenisch, R., Gimbelbrandt, A., Mitalipova, M., and Lee, J.T. (2012). “Molecular signatures and epigenetic stability of human induced pluripotent stem cells.” Cell Stem Cell 11(1):75-90. PMCID: PMC3587778
  • Lessing, D., Anguera, M.C., and Lee, J.T. (2013). “X Chromosome Inactivation and Epigenetic Responses to Cellular Reprogramming.” Annu Rev Genomics Hum Genet. 14:85-110.

3. Mechanisms of X-Chromosome Inactivation in lymphocytes and other immune cells. As an associate professor at Penn, I have continued investigating the molecular mechanisms of X-Chromosome Inactivation, and how altered dosage of X-linked genes contributes to sex-biased disease. As auto-antigen driven activation of lymphocytes drives autoimmune disease we first investigated the epigenetic status of the inactive X in female lymphocytes from humans and mice, and made the remarkable discovery that these cells do not maintain X-Chromosome Inactivation in the same way as other female somatic cells. We were the first to discover that the inactive X has euchromatic features in female lymphocytes, which may underlie the female-bias in autoimmune disorders including lupus. Our research also demonstrated that T and B cells, upon antigen-mediated stimulation, exhibit relocalization of Xist RNA and heterochromatic marks to the inactive X chromosome, which we have termed ‘dynamic XCI maintenance’. My lab is investigating the molecular details of dynamic XCI maintenance in T and B cells, and has identified protein factors that are required for localization of epigenetic modifications to the inactive X.

  • Wang, J., Syrett, C.M., Kramer, M. Basu, A., Atchison, M. & Anguera, M.C. (2016). “Unusual maintenance of X-chromosome Inactivation predisposes female lymphocytes for increased expression from the inactive X”. Proc Natl Acad Sci, Mar. 21, 2016. PMCID: PMC4833277
  • Syrett, C.M., Sindhava, V., Hodawadekar, S., Myles, A., Liang, G., Zhang, Y., Nandi, S., Cancro, M., Atchison, M., & Anguera, M.C. (2017) “Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells”. Plos Genetics, Oct 9; 13 (10). PMCID: PMC5648283
  • Camille Syrett, Vishal Sindhava, Isabel Sierra, Aimee Dubin, Michael Atchison, and Montserrat C. Anguera (2018). “Diversity of Epigenetic Features of the inactive X-chromosome in NK cells, dendritic cells, and macrophages”. Frontiers in Immunology. Dec 14. PMCID: PMC6331414.
  • Sierra I, Anguera MC. (2019). “Enjoy the silence: X-chromosome inactivation diversity in somatic cells.” Curr Opin Genet Dev. 2019 Apr;55:26-31. Epub 2019 May 17. Review. PubMed PMID: 31108425; PubMed Central PMCID: PMC6759402.

4. Impact of autoimmune disease on X-Chromosome Inactivation mechanisms
We continue to investigate diseases exhibiting a female bias that also have abnormal increased expression of X-linked genes. My lab has focused on the autoimmune disorder systemic lupus erythematosus (SLE), which has a strong female-bias and exhibits aberrant over-expression of the X-linked genes CXCR3, CD40LG, TLR7, and FOXP3 in lymphocytes. We made the remarkable discovery that female SLE patients and mouse models with lupus-like disease have perturbations with markers of the inactive X, most notably XIST/Xist RNA localization and heterochromatic modifications H3K27me3 and H2AK119ubiquitin. Our work also found female-specific X-linked gene signatures of SLE patients. We are actively continuing this work in an effort to understand how transcription from the inactive X contributes to autoimmune disease susceptibility and disease severity, and also investigate mouse models of spontaneous lupus disease to examine how disease onset impacts XCI maintenance and X-linked gene expression.

  • Syrett CM, Paneru B, Sandoval-Heglund D, Wang J, Banerjee S, Sindhava V, Behrens EM, Atchison M, & Anguera M.C. (2019) “Altered X-chromosome Inactivation in T cells may promote sex-biased autoimmune diseases”. JCI Insight, Apr 4;4(7). PMCID: PMC6483655.
  • Syrett CM, Sierra I, Beethem ZT, Dubin AH, Anguera MC. “Loss of epigenetic modifications on the inactive X chromosome and sex-biased gene expression profiles in B cells from NZB/W F1 mice with lupus-like disease.” J Autoimmun. (2020) Feb;107:102357. Epub 2019 Nov 25. PubMed PMID: 31780316; PubMed Central PMCID: PMC7237307.
  • Pyfrom S, Paneru B, Knoxx, J, Posso S, Buckner J, Cancro M, Anguera MC. “The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients”. Proc Natl Acad Sci. (2021) June;Vol.118.
  • Jiwrajka N, Anguera MC. “The X in SeX-Biased Immunity and Autoimmune Rheumatic Disease.” J Exp Med. (2022). Review. doi 10.1084/jem.20211487.

Research Interest

My research program focuses on epigenetic gene regulation that underlies sex differences in development and disease. In particular, I am interested in understanding how gene expression from the X-chromosome is regulated to ensure dosage compensation between males and females, and how these mechanisms become altered in diseases exhibiting a sex-bias, such as autoimmunity. We investigate the female-specific epigenetic process of X-chromosome Inactivation (XCI). The X-chromosome contains genes necessary for cell proliferation, metabolism, cognition, reproduction, and has the highest density of immunity-related genes. Thus, gene expression from the X-chromosome is critical for cellular identity, and XCI ensures proper dosage of these genes in females. Abnormal expression of X-linked genes is a feature of many diseases exhibiting a sex-bias, including cancer, cardiovascular disease, and autoimmunity. I have a broad background in epigenetics, spanning the metabolism of one-carbon units that generate methyl groups that alter gene expression, to the epigenetic regulatory mechanisms involved in XCI. My independent research program at the University of Pennsylvania continues to investigate the epigenetic mechanisms that regulate X-linked gene expression, and how alterations result in female-biased disease. My laboratory has undertaken and completed studies establishing a new field of research, defining novel epigenetic pathways involving the X-chromosome that impact human development, immune responses during development, and lymphocyte function. We routinely use RNA and DNA fluorescence in situ hybridization, immunofluorescence experiment, and allele-specific RNA sequencing, which enables single-cell resolution of the epigenetic characteristics of the inactive X and transcriptional activity. Our long-term goal is to understand how dosage compensation of X-linked genes is maintained in lymphocytes, how perturbations with this silencing contribute to female-biased autoimmune disease, and how XCI maintenance mechanisms can be targeted to correct aberrant X-linked gene expression.

Ongoing Projects:
R01 AI134834
Anguera (PI)
6/01/2018-5/31/2023
Gene regulation from the inactive X in activated B cells

Lupus Mechanisms and Targets Award
Anguera (PI)
6/1/2020-5/30/2023
Targeting the inactive X for correcting dosage imbalances in lupus

Jonathan A. Epstein, M.D.

1. We have demonstrated that engineered T cells (CART cells) can be used to target activated fibroblasts in the diseased heart with resulting improvement in cardiac function. This work has received significant attention (highlighted in the NEJM, Scientific American, the NYTimes and elsewhere) and has opened the field of CART cells to the possibility of providing new treatments for fibrotic disorders.
Rurik JG, Tombácz I, Yadegari A, Méndez Fernández PO, Shewale SV, Kimura T, Younoss SO, Papp TE, Tam YK, Mui BL, Albelda SM, Pure E, June CH, Aghajanian H, Weissman D, Parhiz H, Epstein JA. CAR T cells produced in vivo to treat cardiac injury. Science. 2022 Jan 7;375(6576):91-96. doi: 10.1126/science.abm0594
Rurik JG, Aghajanian H, Epstein JA. Immune cells and immunotherapy for cardiac injury and repair. Circ. Res. 2021 May 28; 128(11):1766-1779. Review
Epstein JA, Rosenthal N, Feldman AM. Teasing the Immune System to Repair the Heart. N Engl J Med. 2020 Apr 23;382(17):1660-1662. Review
Aghajanian H, Kimura T, Rurik JG, Hancock AS, Leibowitz MS, Li L, Scholler J, Monslow J, Lo A, Han W, Wang T, Bedi K, Morley MP, Linares Saldana RA, Bolar NA, McDaid K, Assenmacher CA, Smith CL, Wirth D, June CH, Margulies KB, Jain R, Puré E, Albelda SM, Epstein JA. Targeting cardiac fibrosis with engineered T cells. Nature. 2019 Sep;573(7774):430-433. PMCID: PMC6752964

2. We have elucidated the role of epigenetics in heart development and we have applied this knowledge to explore novel therapies for adult cardiac disease including ischemia-reperfusion and congestive heart failure. In particular, we demonstrated that histone deacetylase inhibitors can prevent pathologic cardiac hypertrophy, which was counter to the prevailing dogma at the time. More recently, we have shown that nuclear architecture (how chromatin is packaged in three dimensions in the nucleus) contributes to cell identity, gene expression, and developmental competence.
Smith, C.L., Poleshko, A., Epstein, J.A. The nuclear periphery is a scaffold for tissue-specific enhancers. Nucleic Acids Res. 2021; 49: 6181-6195. PMCID: PMC8216274
Poleshko, A., Shah, P.P., Gupta, M., Babu, A., Moreley, M., Manderfield, L.J., Ifkovits, J.L., Dubois, N., Morrisey, E.E., Lazar, M.A., Smith, C.L., Epstein, J.A., Jain, R. Genome–nuclear lamina interactions regulate progenitor cell lineage restriction during cardiogenesis. Cell. 2017 Oct 7. (co-senior author and mentor of first author). PMCID: PMC5683101
Kook H, Lepore JJ, Gitler AD, Lu MM, Wing-Man Yung W, Mackay J, Zhou R, Ferrari V, Gruber P, Epstein JA. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. The Journal of Clinical Investigation. 2003;112(6):863-71. PMCID: PMC193673.
Chen F, Kook H, Milewski R, Gitler AD, Lu MM, Li J, Nazarian R, Schnepp R, Jen K, Biben C, Runke G, Mackay JP, Novotny J, Schwartz RJ, Harvey RP, Mullins MC, Epstein JA. Hop is an unusual homeobox gene that modulates cardiac development. Cell. 2002;110(6):713-23.

3. My laboratory has contributed to our understanding of how the neural crest influences cardiac development and to the embryologic and genetic basis of congenital heart disease. Neural crest contribution to the heart was described in the early 1980s by Kirby and colleagues, and our laboratory extended these observations to mammalian systems, performed genetic fate-mapping in mouse models, identified candidate genes for congenital heart defects and described molecular pathways including Notch, Fgf, Wnt and Hippo that regulate cross-talk between neural crest, endothelium and second heart field derivatives in the heart.
Manderfield LJ, Engleka KA, Aghajanian H, Gupta M, Yang S, Li L, Baggs JE, Hogenesch JB, Olson EN, Epstein JA. Pax3 and hippo signaling coordinate melanocyte gene expression in neural crest. Cell Reports. 2014;9(5):1885-95. PMCID: PMC4267159.
Manderfield LJ, High FA, Engleka KA, Liu F, Li L, Rentschler S, Epstein JA. Notch activation of Jagged1 contributes to the assembly of the arterial wall. Circulation. 2012;125(2):314-23. PMCID: PMC3260393.
Katz TC, Singh MK, Degenhardt K, Rivera-Feliciano J, Johnson RL, Epstein JA, Tabin CJ. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Developmental Cell. 2012;22(3):639-50. PMCID: PMC3306604.
de la Pompa JL, Epstein JA. Coordinating tissue interactions: Notch signaling in cardiac development and disease. Developmental Cell. 2012;22(2):244-54. PMCID: PMC3285259.

4. We described the molecular basis for cardiovascular manifestations in Type 1 Neurofibromatosis using mouse and zebrafish models, including valvular pulmonic stenosis, endothelial defects and cardiac hypertrophy. We generated a zinc-finger knockout of the Nf1 genes in zebrafish, and demonstrated behavioral defects amenable to small molecule drug screening.
Wolman MA, de Groh ED, McBride SM, Jongens TA, Granato M, Epstein JA. Modulation of cAMP and ras signaling pathways improves distinct behavioral deficits in a zebrafish model of neurofibromatosis type 1. Cell Reports. 2014;8(5):1265-70. PMCID: PMC5850931
Shin J, Padmanabhan A, de Groh ED, Lee JS, Haidar S, Dahlberg S, Guo F, He S, Wolman MA, Granato M, Lawson ND, Wolfe SA, Kim SH, Solnica-Krezel L, Kanki JP, Ligon KL, Epstein JA, Look AT. Zebrafish neurofibromatosis type 1 genes have redundant functions in tumorigenesis and embryonic development. Disease Models & Mechanisms. 2012;5(6):881-94. PMCID: PMC3484870.
Ismat FA, Xu J, Lu MM, Epstein JA. The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1 mice. The Journal of Clinical Investigation. 2006;116(9):2378-84. PMCID: PMC1533876.
Gitler AD, Zhu Y, Ismat FA, Lu MM, Yamauchi Y, Parada LF, Epstein JA. Nf1 has an essential role in endothelial cells. Nature Genetics. 2003;33(1):75-9. PMCID: PMC3079412.

5. We were among the first to show that guidance molecules known to regulate the migration of axons in the central nervous system can also regulate angiogenesis and cardiac development. We have shown that members of the semaphorin and plexin families help to pattern the outflow tract of the heart, the pulmonary veins and coronary arteries, and the peripheral vasculature.
Epstein JA, Aghajanian H, Singh MK. Semaphorin signaling in cardiovascular development. Cell Metabolism. 2015;21(2):163-73. Review
Aghajanian H, Choi C, Ho VC, Gupta M, Singh MK, Epstein JA. Semaphorin 3d and semaphorin 3e direct endothelial motility through distinct molecular signaling pathways. The Journal of Biological Chemistry. 2014;289(26):17971-9. PMCID: PMC4140303.
Degenhardt K, Singh MK, Aghajanian H, Massera D, Wang Q, Li J, Li L, Choi C, Yzaguirre AD, Francey LJ, Gallant E, Krantz ID, Gruber PJ, Epstein JA. Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections. Nature Medicine. 2013;19(6):760-5. PMCID: PMC3746328.
Gitler AD, Lu MM, Epstein JA. PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Developmental Cell. 2004;7(1):107-16.

Research Interest

The Epstein laboratory studies molecular mechanisms of cardiovascular development and stem cell biology, and the implications of these mechanisms for understanding human disease. The lab has a longstanding interest in the genetic causes of congenital heart disease and transcriptional regulation of cell fate determination. Most recently, we have focused on epigenetics, including the role of histone deacetylases in cardiac development and adult heart function. Aims of current projects include gaining an understanding of the three-dimensional packaging of DNA and chromatin in the nucleus (“nuclear architecture”), and the regulation of cell differentiation by protein complexes that tether regions of the genome to the nuclear periphery. The lab has pioneered the concept that interactions between the nuclear lamina and the chromatin contribute to the regulation of entire gene programs that define cardiac cell types.

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