Sneha Gopalan

University of Massachusetts Chan Medical School

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Thomas G. Fazzio

University of Massachusetts Chan Medical School

Ronald Conaway

Stowers Institute for Medical Research

Laurence Florens

Stowers Institute for Medical Research

Joan Conaway

University of Kansas Medical Center

Michael P. Washburn

Stowers Institute for Medical Research

Wei Luan

Memorial Sloan Kettering Cancer Center

Karl Simin

University of Massachusetts Chan Medical School

Adwait Anand Godbole

University of Massachusetts Chan Medical School

Kelly D. DeMarco

University of Massachusetts Chan Medical School

Elisa de Stanchina

Memorial Sloan Kettering Cancer Center

Cooperative Institutions

University of Massachusetts Chan Medical School

Harvard University

Howard Hughes Medical Institute

Massachusetts Institute of Technology

Dana-Farber Cancer Institute

Stowers Institute for Medical Research

Memorial Sloan Kettering Cancer Center

Kettering University

National Institutes of Health

University of Calgary

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CUT&RUN and CUT&Tag: Low-input methods for genome-wide mapping of chromatin proteins

Elsevier eBooks (2023)

Sneha Gopalan Thomas G. Fazzio

Chromatin immunoprecipitation

ChIA-PET

Epigenomics

Histone code

ChIP-on-chip

Bivalent chromatin

Histone-modifying enzymes

ChIP-sequencing

10.1016/b978-0-12-823376-4.00010-0

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Schizosaccharomyces pombePol II transcription elongation factor ELL functions as part of a rudimentary super elongation complex

Nucleic Acids Research (2018)

Sneha Gopalan Dana M Gibbon Charles A.S. Banks Ying Zhang Laurence Florens

ELL family transcription factors activate the overall rate of RNA polymerase II (Pol II) transcription elongation by binding directly to Pol II and suppressing its tendency to pause. In metazoa, ELL regulates Pol II transcription elongation as part of a large multisubunit complex referred to as the Super Elongation Complex (SEC), which includes P-TEFb and EAF, AF9 or ENL, and an AFF family protein. Although orthologs of ELL and EAF have been identified in lower eukaryotes including Schizosaccharomyces pombe, it has been unclear whether SEC-like complexes function in lower eukaryotes. In this report, we describe isolation from S. pombe of an ELL-containing complex with features of a rudimentary SEC. This complex includes S. pombe Ell1, Eaf1, and a previously uncharacterized protein we designate Ell1 binding protein 1 (Ebp1), which is distantly related to metazoan AFF family members. Like the metazoan SEC, this S. pombe ELL complex appears to function broadly in Pol II transcription. Interestingly, it appears to have a particularly important role in regulating genes involved in cell separation.

Elongation factor

RNA polymerase II

Transcription

P-TEFb

Schizosaccharomyces

10.1093/nar/gky713

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Citations (7)

S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Adwait Anand Godbole Sneha Gopalan Thien-Kim Nguyen Alexander Munden Paula Vo

Abstract Methylation is a widely occurring modification that requires the methyl donor S-adenosylmethionine (SAM) and acts in regulation of gene expression and other processes. SAM is synthesized from methionine, which is imported or generated through the 1-carbon cycle (1CC). Alterations in 1CC function have clear effects on lifespan and stress responses, but the wide distribution of this modification has made identification of specific mechanistic links difficult. Exploiting a dynamic stress-induced transcription model, we find that two SAM synthases in Caenorhabditis elegans , SAMS-1 and SAMS-4, contribute differently to modification of H3K4me3, gene expression and survival. We find that sams-4 enhances H3K4me3 in heat shocked animals lacking sams-1 , however, sams-1 cannot compensate for sams-4 , which is required to survive heat stress. This suggests that the regulatory functions of SAM depend on its enzymatic source and that provisioning of SAM may be an important regulatory step linking 1CC function to phenotypes in aging and stress.

H3K4me3

10.1101/2022.03.30.486419

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Role of the ELL complex in transcriptional regulation in S. pombe

The FASEB Journal (2017)

Sneha Gopalan Dana M Gibbon Chris Seidel Ying Zhang Laurence Florens

The ELL family of transcription elongation factors can suppress the transient pausing of Pol II at each step of nucleotide addition during transcription, thereby stimulating the overall rate of transcription. ELL‐associated factors (EAFs) bind directly to ELL and are positive regulators of ELL elongation activity. ELL and EAF have been implicated in the release of RNA pol II from promoter proximal pausing by an unknown mechanism. Orthologs of ELL and EAF were not identified in fungi until recently. Previous data from our lab identified genes in S. pombe similar to ELL and EAF, which have no obvious orthologs in S. cerevisiae . SpELL and SpEAF also interact with each other to form a heterodimer and can positively regulate transcription by RNA pol II. We identified proteins interacting with SpELL and SpEAF by immunoprecipitation followed by Multidimensional Protein Identification Technology (MudPIT). Proteomic analyses revealed an uncharacterized sequence orphan protein that associates strongly with both ELL and EAF. Biochemical analysis using recombinant proteins confirmed that this protein binds directly to ELL and forms a ternary complex with ELL and EAF. ChIP‐seq experiments suggest that all three proteins co‐localize at genes with high RNA pol II occupancy. Synthetic Genetic Array (SGA), a high‐throughput technique for exploring genetic interactions, was performed on the deletion mutants lacking the genes encoding ELL, EAF and the novel ELL‐interacting protein. Preliminary data analysis suggests that these genes may interact genetically with overlapping set of genes. Support or Funding Information

Transcription

RNA polymerase II

10.1096/fasebj.31.1_supplement.593.12

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Cryo-EM structure of the Mediator-RNAPII complex

Kuang‐Lei Tsai Xiaozhen Yu Sneha Gopalan Ti‐Chun Chao Yang Zhang

10.2210/pdb5u0s/pdb

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EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Loretah Chibaya Katherine Murphy Yvette Lopez-Diaz Kelly D. DeMarco Haibo Liu

ABSTRACT T cell-activating immunotherapies that produce durable and even curative responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP) can be an effective approach to activate not only T cell but also cytotoxic Natural Killer (NK) cell-mediated anti-tumor immunity. Here we found that the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated repression of pro-inflammatory SASP genes. Genetic or pharmacological inhibition of EZH2 or its methyltransferase activity stimulated the production of pro-inflammatory SASP chemokines CCL2 and CXCL9/10 that led to enhanced NK and T cell infiltration and tumor eradication in preclinical PDAC mouse models. EZH2 activity was also associated with suppression of SASP-associated inflammatory chemokines and cytotoxic lymphocyte immunity and reduced overall survival in a PDAC patient cohort. These results demonstrate that EZH2 mediates epigenetic repression of the pro-inflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with senescence-inducing therapies could be a powerful means to potentiate NK and T cell surveillance in PDAC to achieve immune-mediated tumor control.

Senescence

10.1101/2022.06.21.495523

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Citations (3)

Revisiting chromatin packaging in mouse sperm

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Qiangzong Yin Chih-Hsiang Yang Olga Strelkova Jingyi Wu Yu Sun

ABSTRACT Mammalian sperm exhibit an unusual and heavily-compacted genomic packaging state. In addition to its role in organizing the compact and hydrodynamic sperm head, it has been proposed that sperm chromatin architecture helps to program gene expression in the early embryo. Scores of genome-wide surveys in sperm have reported patterns of chromatin accessibility, histone localization, histone modification, and chromosome folding. Here, we revisit these studies in light of recent reports that sperm obtained from the mouse epididymis are contaminated with low levels of cell-free chromatin. In the absence of proper sperm lysis we readily recapitulate multiple prominent genome-wide surveys of sperm chromatin, suggesting that these profiles primarily reflect contaminating cell-free chromatin. Removal of cell-free DNA, along with appropriate lysis conditions, are required to reveal a sperm chromatin state distinct from most previous reports. Using ATAC-Seq to explore relatively accessible genomic loci, we identify a landscape of open loci associated with early development and transcriptional control. Histone modification and chromosome folding studies also strongly support the hypothesis that prior studies suffer from contamination, but technical challenges associated with reliably preserving the architecture of the compacted sperm head prevent us from confidently assaying true localization patterns for these epigenetic marks. Together, our studies strongly argue that our knowledge of mammalian chromosome packaging remains largely incomplete, and motivate future efforts to more accurately characterize genome organization in mature sperm.

Chromosome conformation capture

10.1101/2022.12.26.521943

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Citations (4)

Multi-CUT&Tag to simultaneously profile multiple chromatin factors

STAR Protocols (2022)

Sneha Gopalan Thomas G. Fazzio

Genome-wide chromatin mapping approaches typically focus on one protein at a time. We recently developed multi-CUT&Tag, which enables simultaneous mapping of multiple chromatin proteins in the same single cells or pools of cells. Using barcoded adapters loaded onto antibody-protein A-Tn5 transposase complexes, multi-CUT&Tag marks the locations of each chromatin protein and directly detects colocalization of different proteins in the same cell(s). Although slightly more laborious than CUT&Tag, multi-CUT&Tag provides a powerful option for generating multi-factor maps for epigenomic profiling. For complete details on the use and execution of this protocol, please refer to Gopalan et al. (2021).

Colocalization

Epigenomics

Profiling (computer programming)

Transposase

10.1016/j.xpro.2021.101100

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Citations (6)

EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

Nature Cancer (2023)

Loretah Chibaya Katherine Murphy Kelly D. DeMarco Sneha Gopalan Haibo Liu

Proinflammatory cytokine

Senescence

10.1038/s43018-023-00553-8

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Citations (55)

S-adenosylmethionine synthases specify distinct H3K4me3 populations and gene expression patterns during heat stress

eLife (2023)

Adwait Anand Godbole Sneha Gopalan Thien-Kim Nguyen Alexander Munden Dominique S. Lui

Methylation is a widely occurring modification that requires the methyl donor S-adenosylmethionine (SAM) and acts in regulation of gene expression and other processes. SAM is synthesized from methionine, which is imported or generated through the 1-carbon cycle (1 CC). Alterations in 1 CC function have clear effects on lifespan and stress responses, but the wide distribution of this modification has made identification of specific mechanistic links difficult. Exploiting a dynamic stress-induced transcription model, we find that two SAM synthases in Caenorhabditis elegans, SAMS-1 and SAMS-4, contribute differently to modification of H3K4me3, gene expression and survival. We find that sams-4 enhances H3K4me3 in heat shocked animals lacking sams-1, however, sams-1 cannot compensate for sams-4, which is required to survive heat stress. This suggests that the regulatory functions of SAM depend on its enzymatic source and that provisioning of SAM may be an important regulatory step linking 1 CC function to phenotypes in aging and stress.

H3K4me3

10.7554/elife.79511

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Citations (6)