Martin J Walsh, PhD
- ASSOCIATE PROFESSOR | Pharmacological Sciences
- ASSOCIATE PROFESSOR | Pediatrics, Hepatology
- ASSOCIATE PROFESSOR | Genetics and Genomic Sciences
Research Topics:Apoptosis/Cell Death, Bioinformatics, Cancer, Cell Cycle, Cell Division, Cellular Differentiation, Chromatin, Developmental Biology, Drug Design and Discovery, Epigenetics, Gene Regulation, Human Genetics and Genetic Disorders, Mass Spectrometry, Mitosis, Nucleus, Oncogenes, Protein Structure/Function, Proteomics, RNA, Transcription Factors, Transcriptional Activation and Repression
Multi-Disciplinary Training AreasBiophysics and Systems Pharmacology [BSP], Genetics and Genomic Sciences [GGS]
BS, State University of New York at Buffalo
PhD, Columbia University
Senior Scholar Award in Aging
Perpetuation of cellular self -renewal by the ZNF217 oncogene-
ZNF21/zfp217 is an important oncogene in many cancer types. It impacts cell physiology markedly by shifting the apoptotic threshold of cancer cells causing resistance to the chemotherapeutical agent doxorubicin and contributing to telomere stability and immortalization under certain experimental conditions. While recent observations are clearly relevant to the understanding of ZNF217's role(s) in cancer, they represent an indirect effect through ZNF217's aggregate activity on the large number of genes that it targets. Little is known about how ZNF217 operates at the level of individual genes, i.e., about its principal mode(s) of molecular action as transcription factor. We have now demonstrated that ZNF217 forms a nuclear complex that can modify histones. Specifically, we documented H3K4me3 demethylation; H3K9 methylation; and H3K27 methylation. We identified five nuclear proteins contained in the ZNF217 complex, namely Jarid1b/Plu-1, a histone H3 lysine 4 (H3K4) tri-methyl demethylase; G9a, a principal euchromatic H3K9 methylase EZH2, a H3K27 methylase associated with the Polycomb Repressive Complex 2 (PRC2); LSD1, a H3K4 demethylase; CtBP1 and CoREST, which are both transcriptional co-repressors. Our studies illuminate the view that ZNF217 adopts a dynamic configuration of chromatin modifying enzymes to adapt to the localized chromatin environment. In collaboration with Dr. Gail Mandel's laboratory (Vollum Institute), we have now directed the ablation of the ZNF217 orthologue zfp217 in mouse embryonic stem cells
Epigenetic programming of Polycomb through long non -coding RNAs-
More recent studies investigate the regulation of the Polycomb group (PcG) and Trithorax (Trx) proteins in exerting gene control through the coordination of binding between long non-coding RNAs, histone lysine methylation and ubiquitination during early embryonic development and during oncogenesis. We have recently directed our effort to understand the role of long non-coding RNAs (ncRNAs) to mediate the function of Polycomb Repressive Complexes (PRCs) 1 and 2. Transcription is pervasive through out the mammalian genome, however, most transcripts are non-coding in the genome but have been thought to impose an architectural function in chromatin Our recent studies have shown that ncRNAs are an instructional component of chromatin that mediates the function of PRC1 and PRC2 to further impose histone modifications for epigenetic gene silencing. Current studies by RNA ChIP-Seq are evaluating the role of ncRNAs that mask the human genome to coordinate PRC function during development and in human disease.
The Modulation of Chromatin Structure and Function in Transcription
The capacity to reprogram gene expression programs determine the fate of cells to self renew, differentiate or terminate. The transcription of genetic information from DNA is the fundamental process that regulates gene expression and requires elaborate and complex signals necessary to overcome the normally repressive state of chromatin. Our laboratory has focused on understanding the mechanisms that regulate gene expression through processes that recognize and establish epigenetic character in chromatin necessary to facilitate or repress gene transcription. Much of our recent work has been in close collaboration with Ming-Ming Zhou to adopt innovative approaches that will understand the molecular, structural and biochemical basis for epigenetic control of gene expression. Recently, our studies solved the molecular structure and the biochemical function of the SWIRM domain, a phylogenetically conserved structure common in many chromatin-associated proteins. Much of our ongoing effort has been to combine structure -guided analysis that will utilize chemistry-based experimental designs to determine the molecular and cellular function of chromatin proteins in vivo in a more effective manner. Future studies plan to exploit the physical structure of proteins that interact with DNA, RNA and modified histones and to use chemical probes to assess their biochemical and cellular function in a native cellular environment. Ongoing studies also exploit the use of chromatin immunoprecipitation sequencing (ChIP-Seq) and high -density sequencing maps to determine the global impact on cellular chromatin. Below is a brief summary of ongoing projects in the laboratory.
Regulation of chromatin structure by human CUTL1 transcription factor-
Our focus has been directed on two fundamental transcription factors that play key roles in both oncogenic transformation and during development called the CCAAT displacement protein/cut homologue (CUTL1) and zinc finger protein 217 (ZNF217/zfp217). CUTL1 in man and cux in mouse are essential for development and self -renewal in various tissue compartments in metazoan vertebrates. CUTL1 is also a key determinant in promoting tumor cell migration and metastasis. We have previously shown that CUTL1 can mediate the acetylation and methylation of nucleosomal histones through the differential recruitment and of histone acetyltransferase (HAT), histone deacetylase (HDAC), and histone lysine metyltransferase (HMT) activities. We have also demonstrated that CUTL1 is a substrate of many of these enzymes that determine the function of CUTL1. Although, transcription factors have the ability to bind DNA they typically lack the capacity to navigate chromatin structure necessary to access cognate DNA sequences. Many transcriptional co-regulators provide the function to recognize and bind post-translational -modified nucleosomal histone. When tethered to co-regulators, transcription factors attain the ability to associate with highly ordered chromatin structure and impose their regulatory function. Our ongoing studies are investigating the role novel nuclear co-regulators and their conserved protein domains that can "read" the histone code by binding modified histone residues that mark functional domains within chromatin. Identification and analysis by ChIP-Seq of transcriptional co-regulators for CUTL1 and the histone marks they impose will help us determine the "visual scope" and native context for CUTL1 occupation within the human genome.
Li D, Li S, Yea S, Chen Z, Narla G, Banck M, Laborda J, Tan S, Friedman JM, Friedman SL, Walsh MJ. KLF6 promotes preadipocyte differentiation through histone deacetylase 3 (HDAC3)-dependent repression of dlk1. J. Bio Chem 2005; 280: 26941-26952.
Li D, Yea S, Dolios G, Li S, Martignetti JA, Narla G, Wang R, Walsh MJ, Friedman S. Regulation of Kruppel -like factor 6 tumor suppressor activity by acetylation. Cancer Res 2005; 65: 9216-9225.
Qian C, Zhang Q, Li S, Zeng L, Walsh MJ, Zhou MM. Structure and chromosomal binding of the SWIRM domain. Nat. Struct. Mol. Bio 2005; 12: 1078-1085.
Paul T, Li S, Khurana S, LeLeiko NS, Walsh MJ. The epigenetic signature of CFTR expression is coordinated via chromatin acetylation through a complex intronic element. Biochem. J 2007; 408: 317-328.
Walsh MJ, Licht JD. The multiple myeloma SET domain (MMSET) protein is a histone methyltransferase with characteristics of a transcriptional co-repressor. Blood 2008; 111: 3145-3154.
Tan C, Sindhui KV, Li S, Nishio H, Stoller JS, Oishi K, Puttreddy K, Lee TJ, Epstein J, Walsh MJ, Gelb B. Transcription Factor Ap2o Associates with Ash2l and ALR, a Trithorax Family Histone Methyltransferase, to Activate Hoxc8 Transcription. Proc. Natl. Acad Sci. USA 2008; 105: 7472-7477.
Pless O, Kowenz-Leutz E, Knoblich M, Lausen J, Beyermann M, Walsh MJ, Leutz A. G9a mediated lysine methylation alters the function of CCAAT/Enhancer B -binding protein (C/EBPB). J. Bio. Chem 2008; 283: 26357-26367.
Banito A, Rashid ST, Acosta JC, Li S, Pereira CF, Geti I, Pinho S, Silva JC, Azuara V, Walsh MJ, Gil J. Senescence impairs successful reprogramming to pluripotent stem cells. Genes Dev. 2009; 23: 2134-2139.
Banck MS, Li S, Nishio N, Wang C, Beutler AS, Walsh MJ. The ZNF217 oncogene is a candidate organizer of repressive histone modifiers. Epigenetics 2009; 4: 1-9.
Yap K, Li S, Munoz-Cabello A, Raguz S, Zeng LJ, Mujtaba S, Gil JA, Walsh MJ, Zhou M. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by Polycomb CBX7 in Ttranscriptional silencing of INK4a. Molecular Cell 2010; 38: 1-13.
Zeng L, Li S, Walsh MJ, Zhou M. Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b. Nature 2010 July; 466: 258-262.
Ren C, Morohashi K, Plotnikov AN, Jakoncic J, Smith SG, Li J, Zeng L, Rodriguez Y, Stojanoff V, Walsh M, Zhou MM. Small-molecule modulators of methyl-lysine binding for the CBX7 chromodomain. Chemistry & biology 2015 Feb; 22(2).
Sancho A, Li S, Paul T, Zhang F, Aguilo F, Vashisht A, Balasubramaniyan N, Leleiko NS, Suchy FJ, Wohlschlegel JA, Zhang W, Walsh MJ. CHD6 regulates the topological arrangement of the CFTR locus. Human molecular genetics 2015 May; 24(10).
Aguilo F, Di Cecilia S, Walsh MJ. Long Non-coding RNA ANRIL and Polycomb in Human Cancers and Cardiovascular Disease. Current topics in microbiology and immunology 2015 Jul;.
Aguilo F, Zhang F, Sancho A, Fidalgo M, Di Cecilia S, Vashisht A, Lee DF, Chen CH, Rengasamy M, Andino B, Jahouh F, Roman A, Krig SR, Wang R, Zhang W, Wohlschlegel JA, Wang J, Walsh MJ. Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming. Cell stem cell 2015 Oct;.
Aguilo F, Li S, Balasubramaniyan N, Sancho A, Benko S, Zhang F, Vashisht A, Rengasamy M, Andino B, Chen CH, Zhou F, Qian C, Zhou MM, Wohlschlegel JA, Zhang W, Suchy FJ, Walsh MJ. Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α. Cell reports 2016 Jan;.
Kent B, Magnani E, Walsh MJ, Sadler KC. UHRF1 regulation of Dnmt1 is required for pre-gastrula zebrafish development. Developmental biology 2016 Feb;.
Ren C, Smith SG, Yap K, Li S, Li J, Mezei M, Rodriguez Y, Vincek A, Aguilo F, Walsh MJ, Zhou MM. Structure-Guided Discovery of Selective Antagonists for the Chromodomain of Polycomb Repressive Protein CBX7. ACS medicinal chemistry letters 2016 Jun; 7(6).