Kahlilia Blanco, Ph.D.

Research Interest

Stroke is a devastating neurological disease that affects millions of individuals every year and causes severe disability or death. Unfortunately, effective stroke treatments are limited and many stroke survivors are left with major neurological impairments that decrease their quality of life. Therefore, improved clinical therapies are necessary for stroke survivors to achieve longer, healthier lives.

Scientific evidence over the last decade has revealed that epigenetics play a major role in stroke injury. Epigenetics are modifications to DNA that can cause either increases or decreases in gene expression. Epigenetic modifications have been shown to produce large-scale changes in gene expression after stroke and significantly influence post-stroke recovery. The goal of our research program is to mechanistically investigate epigenetic factors involved in neuroprotection and determine their potential as stroke therapeutics.

Richard Phillips, M.D., Ph.D.

  1. Identification of oncogenic pathways as therapeutic targets in epigenetically driven gliomas

I investigated the mechanism of action of a menin-inhibitor, MI-2, in H3K27M gliomas following up on studies which identified a menin-inhibitor (MI-2) as the top ‘hit’ in a chemical screen in a new model of this disease (Funato et. al, 2014, Science). Menin is an epigenetic regulator which we hypothesized may be specifically required in the setting of H3K27M induced epigenetic dysregulation. I demonstrated that MI-2 exhibits anti-glioma activity in H3K27M mutant and H3 wild-type glioma subtypes and showed menin is not the relevant molecular target for this drug in gliomas. Instead, using an integrated approach employing genetic, biochemical and metabolomic methods, I discovered the direct molecular target of MI-2 in glioma as lanosterol synthase, a cholesterol biosynthesis enzyme; revealing a novel metabolic vulnerability in glioma and more broadly implicating cholesterol homeostasis as an attractive pathway to target in this malignancy. 

Phillips RE, Yang Y, Smith R, Thompson B, Yamasaki T, Soto-Feliciano Y, Funato K, Liang Y, Garcia-Bermudez J, Wang X, Garcia B, Yamasaki K, McDonald J, Birsoy K, Tabar V, Allis CD. Target identification reveals lanosterol synthase as a vulnerability in glioma. Proc Natl Acad Sci U S A. 2019 Apr 16;116(16):7957-7962. PMCID: PMC6475387

Phillips RE, Soshnev AA, Allis CD. Epigenomic Reprogramming as a Driver of Malignant Glioma. Cancer Cell. 2020 Aug 31:S1535-6108(20)30419-0.

  1. Development of novel therapeutics in glioma targeting epigenetic mechanisms

We identified the chromatin regulator EZH2 as a context-specific dependency in H3K27M gliomas and through computational modeling of existing, non-brain penetrant EZH2 inhibitor scaffolds, and I led a collaboration which devised a chemical strategy resulting in the discovery of the first brain-penetrant small molecule targeting EZH2 for brain tumors.

A Chemical Strategy toward Novel Brain-Penetrant EZH2 Inhibitors. Liang R, Tomita D, Sasaki Y, Ginn J, Michino M, Huggins DJ, Baxt L, Kargman S, Shahid M, Aso K, Duggan M, Stamford AW, DeStanchina E, Liverton N, Meinke PT, Foley MA, Phillips RE. ACS Med Chem Lett. 2022 Feb 10;13(3):377-387. PMCID: PMC4981478

  1. Treatment approaches for management of brain tumors

Medulloblastoma is the most common primary brain tumor in children and management of extra-neural recurrence is a controversial and difficult-to-treat clinical scenario in Neuro-Oncology. We demonstrated efficacy of a combination standard-dose chemotherapy regimen which obviated the need for high-dose chemotherapy and stem cell transplantation (which both have significant potential side-effects) to induce long-term remission in this clinical entity.

Phillips RE, Curran KJ, Khakoo Y. Management of late extra-neural recurrence of medulloblastoma without high-dose chemotherapy. J Neurooncol. 2015 Sep;124(3):523-4. PMCID: PMC4981478


Coordinated epigenetic regulation enables cells to adopt specific gene expression programs to orchestrate normal differentiation and maintain cell fate. Gliomas are the most common type of brain cancer and exome-sequencing data has identified mutations in epigenetic regulators as a major driver of these tumors. However, it remains incompletely understood how these epigenetic drivers rewire the chromatin landscape and how this epigenetic dysregulation alters cellular phenotypes such as differentiation and immune evasion. In the Phillips Lab, we employ a number of cutting-edge techniques – from the development of forward genetics tools (i.e. CRISPR-Cas9 screening technology), epigenomic profiling, using neural stem cell models, and patient-derived models of glioma – to elucidate how epigenetic mechanisms contribute to gliomagenesis. Our long term research goal is to understand the how epigenetic pathways are rewired in brain cancer during tumorigenesis, therapy, and evasion of immunity.

Erica Korb, Ph.D

The role of chromatin in neurodevelopmental disorders and disease.

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

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

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

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

Epigenetic regulation of information storage in the brain

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

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

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

Linking the synapse to the nucleus.

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

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

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

Research Interest

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

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.

Shelley L. Berger, Ph.D.

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. Cell184:6081-6100.

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.

Marisa Bartolomei, Ph.D.

The work in my laboratory focuses on elucidating the mechanisms governing genomic imprinting in mammals. Imprinted genes number in the hundreds, are largely located in domains and are expressed from a single parental allele. This monoallelic gene expression pattern is set in the gametes and maintained during development using epigenetic mechanisms such as DNA methylation and posttranslational histone modifications. Genomic imprinting is an excellent model for studying epigenetic gene regulation during mammalian development. We have used mouse models with mutations in cis-acting regulatory sequences and trans-acting epigenetic factors to study imprinted gene regulation, including examining tissue-specific effects and higher order chromatin structure and architecture. Historically we conducted in depth analyses of the H19Igf2 imprinted locus but have more recently expanded to Grb10Ddc1 locus to reveal cis-acting regulatory elements. For elucidating establishment and maintenance of imprinted gene expression we have studied most of the imprinted loci and incorporated genome-wide approaches and mutations in the DNA methylation machinery. Specifically, we have studied the role of oxidase TET1 in reprogramming of iPSCs and genomic imprints, more recently expanding to study reprogramming of the male germline using a series of Tet1 mutant mice. We have also studied X inactivation in many of these model systems.

Additionally, we use mouse models to study the epigenetic consequences of environmental perturbations such as in utero exposure to endocrine disrupting compounds (EDCs) and Assisted Reproductive Technologies (ART). With respect to EDCs, we have used a mouse model to show that BPA exerts an abnormal metabolic, skeletal health and behavior phenotypes, largely observed in males. In these models we have focused on placenta as well as fetal and postnatal phenotypes. For the ART mouse model, we have studied the long-term outcomes of procedures used in assisted reproduction and have observed sex-specific metabolic and cardiovascular phenotypes and behavioral perturbations as mice age. Moreover, we have shown that embryo culture in the most significant procedure with respect to conferring abnormal DNA methylation profiles in ART-conceived offspring. Finally, we have employed high throughput technologies to study DNA methylation, transcription, chromatin structure and proteomics in a variety of cell types.

Research Interest

The research in the Bartolomei laboratory focuses epigenetic control of genomic imprinting. They also study how the environment can perturb genomic imprinting and other epigenetic processes important in reproduction and health.

Elizabeth Heller, Ph.D.

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.

Jennifer E. Phillips-Cremins, Ph.D.

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.

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