Associate Professor, Department of Molecular Pharmacology
Associate Professor, Department of Cell Biology
THE ROLE OF MACROH2A REGULATION OF CHROMATIN STRUCTURE AND FUNCTION DURING CANCER AND CELLULAR SENESCENCE
The macroH2A-type histone variants (which include macroH2A1.1, macroH2A1.2 and macroH2A2) have roles in tumor suppression, cellular senescence, activation and repression of transcription, promotion of DNA repair and suppression of the reprogramming of differentiated cells into stem cells. MacroH2As are typified by a histone H2A-like region fused by a flexible linker to a C-terminal macrodomain, a ligand-binding domains whose functions are modulated by binding to poly(ADP-ribose) produced by a family of poly(ADP-ribose) polymerases. MacroH2A1 regulates the expression of genes found within its large chromatin domains which can span hundreds of kilobases. MacroH2A1 also plays a critical role in regulating gene expression during oncogene-induced senescence, an important tumor suppressive mechanisms. We recently discovered that during senescence an endoplasmic reticulum (ER) stress-dependent mechanism requiring the DNA damage signaling kinase ATM leads to genome-wide changes in macroH2A1 genomic distribution which resemble that of cancer cells. Through changes in its expression and/or alterations in its genomic localization, disruption of macroH2A1’s tumor suppressive functions are common in cancer; alterations of macroH2A transcription and splicing occur in a variety of cancers including those of lung, breast, colon, ovaries, endometrium, bladder, testicles, and melanocytes. Consistently, macroH2A1 loss in primary cells is sufficient to trigger an oncogenic gene expression profile.
We use a variety of innovative reverse genetics, pharmacological and genome-wide approaches to achieve our overall goals of elucidating the function of macroH2A1 in the regulation of gene expression in normal and senescent cells and to determine how dysregulation of macroH2A1 function contributes to alterations in gene expression that allow senescence-bypass and oncogenesis. Current areas of emphasis in the lab include (1) determining the mechanisms regulating the genome-wide deposition of macroH2A1 into chromatin, (2) determining the mechanism by which macroH2A1-regulation of H2B acetylation regulates enhancer function and transcription, (3) determining the mechanism of ATM activation and macroH2A1 mobilization in response to ER stress during senescence and (4) determining the mechanism by which RNA Pol II elongation rate regulates macroH2A1 splicing. The knowledge about macroH2A1-mediated regulation of gene expression, genomic localization and macroH2A1 splicing regulation gained from our efforts will aid our understanding of how macroH2A1’s functions becomes dysregulated during oncogenesis.
Chen, H., Ruiz, P.D., McKimpson, W.M., Novikov, L., Kitsis, R.N. and Gamble, M.J. (2015) “MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype.” Mol. Cell 59:719-31.
Chen, H., Ruiz, P.D., Novikov, L., Casill, A.D., Park, J.W. and Gamble, M.J. (2014) “MacroH2A1.1 and PARP-1 cooperate to regulate transcription by promoting CBP-mediated H2B acetylation.” Nat. Struct. Mol. Biol. 21:981-9.
Hussey, K.M., Chen, H., Yang, C., Park, E., Hah, N., Erdjument-Bromage, H., Tempst, P., Gamble, M.J.*, Kraus, W.L.* (2014) “The histone variant macroH2A1 regulates target gene expression in part by recruiting the transcriptional coregulator PELP1.” Mol Cell Biol. 34:2437-49.
Gamble, M.J. (2013) Expanding the functional repertoire of macrodomains. Nat Struct Mol Biol 20:407-8
Zhang, T., Berrocal, J.G., Yao, J., DuMond, M.E., Krishnakumar, R., Ruhl, D.D., Gamble, M.J., and Kraus, W.L. (2012) “Regulation of poly(ADP-ribose) polymerase-1-dependent gene expression through promoter-directed recruitment of a nuclear NAD+ synthase.” J. Biol. Chem. 287:12405-16.
Novikov, L., Klerman, H., Jalloh, A.S., and Gamble, M.J. (2011) “QKI-mediated alternative splicing of the histone variant macroH2A1 regulates cancer cell proliferation.” Mol Cell Biol. 31:4244-4255
Zhang, X., Gamble M.J., Stadler, S., Cherrington, B.D., Causey, C.P., Thompson, P.R., Robertson, M.S., Kraus, W.L., Coonrod, S.A. (2011) “Genome-wide analysis reveals PADI4 Cooperates with ELK-1 to activate c-Fos expression in Breast Cancer Cells.” PLoS Genetics. 7:e1002112.
Gamble, M.J. and Kraus, W.L. (2010) “Multiple facets of the unique histone variant macroH2A: from genomics to cell biology.” Cell Cycle 9:2568-2574.
Gamble, M.J., Frizzell, K.M., Yang, C., Krishnakumar, R., Kraus, W.L. (2010) “The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing.” Genes and Development 24:21-32
Frizzell, K.M., Gamble, M.J., Zhang, T., Berrocal, J.G., Zhang, T., Krishnakumar, R., Cen, Y., Sauve, A.A., and Kraus, W.L. (2009) "Global Analysis of Transcriptional Regulation by Poly(ADP-ribose) Polymerase-1 and Poly(ADP-ribose) Glycohydrolase in MCF-7 Human Breast Cancer Cells." Molecular and Cellular Biology. 284:33926-28
Zhang, T., Berrocal, J.G., Frizzell, K.M., Gamble, M.J., Dumond, M.E., Krishnakumar, R., Yang, T., Sauve, A.A., Kraus, W.L. (2009) “Enzymes in the NAD+ Salvage Pathway Regulate SIRT1 Activity at Target Gene Promoters.” J. Biol Chem. 284:20408-17
Krishnakumar, R.*, Gamble, M.J.*,Frizzell, K.M., Berrocal, J.G., Kininis, M., Kraus, W.L. (2008) Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes. Science 319:819-21 (* equal contribution)
Gamble, M.J. and Fisher R.P. (2007) SET and PARP1 remove DEK from chromatin to permit access by the transcription machinery. Nat Struct Mol Biol. 14;548-55
Gamble, M.J. and Kraus W.L. (2007) Visualizing the histone code on LSD1. Cell 128:433-4
Larochelle, S., Batliner, J., Gamble, M.J., Barboza, N.M., Kraybill, B.C., Blethrow, J.D., Shokat, K.M., Fisher, R.P.(2006) Dichotomous but stringent substrate selection by the dual-function Cdk7 complex revealed by chemical genetics. Nat Struct Mol Biol 13:55-62
Gamble, M.J., Erdjument-Bromage, H., Tempst, P., Freedman, L.P., Fisher, R.P. (2005) The histone chaperone, TAF-I/SET, is required for activated transcription in vitro of chromatin templates. Mol Cell Biol 25:797-807
Gamble, M.J., Freedman, L.P. (2002) A coactivator code for transcription. Trends Biochem Sci 27: 165-7.
Rachez, C., Gamble, M.J., Chang, C.P., Atkins, G.B., Lazar, M.A. Freedman, L.P. (2000) The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes. Mol Cell Biol 20:2718-26.
Rachez, C., Lemon, BD., Suldan, Z., Bromleigh, V., Gamble, M., Naar, A.M., Erdjument-Bromage, H., Tempst, P., and Freedman, L.P. (1999) Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398:824-8.
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