The macroH2A1-type histone variants (which include macroH2A1.1 and macroH2A1.2) have roles in tumor suppression, 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. Interestingly, during senescence an 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 is common in cancer; alterations of macroH2A transcription and splicing have been observed 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. The overall goals of this project are to elucidate the function of macroH2A1in 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. A variety of innovative reverse genetics, pharmacological and genome-wide approaches will be used in the pursuit of these goals.
The first aim will determine the mechanisms by which macroH2A1 variants regulate transcription in normal and senescent cells.
The second aim will determine the mechanism of ATM activation and macroH2A1 mobilization in response to ER stress during senescence.
The third aim will determine the mechanism by with 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 this proposal will help to explain how macroH2A1 function becomes dysregulated during oncogenesis.

Public Health Relevance

MacroH2A1, a factor that binds to and regulates genes, plays roles in a variety of important functions in cells including tumor suppression, senescence, the positive and negative regulation of transcription, promotion of DNA repair and differentiation. This proposal aims to determine the mechanisms by which macroH2A1 regulates gene expression, thereby allowing it to perform its cellular functions. Understanding how macroH2A1 function is regulated in normal and senescent cells will aid in the understanding of both how to target senescent cells for clearance and how macroH2A1 function becomes dysregulated in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA155232-08
Application #
9515557
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Okano, Paul
Project Start
2012-05-04
Project End
2022-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
Chen, Hongshan; Ruiz, Penelope D; McKimpson, Wendy M et al. (2015) MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype. Mol Cell 59:719-31
Wang, Wei-Lin; Anderson, Lissa C; Nicklay, Joshua J et al. (2014) Phosphorylation and arginine methylation mark histone H2A prior to deposition during Xenopus laevis development. Epigenetics Chromatin 7:22
Hussey, Kristine M; Chen, Hongshan; Yang, Christine et al. (2014) The histone variant MacroH2A1 regulates target gene expression in part by recruiting the transcriptional coregulator PELP1. Mol Cell Biol 34:2437-49
Chen, Hongshan; Ruiz, Penelope D; Novikov, Leonid et al. (2014) MacroH2A1.1 and PARP-1 cooperate to regulate transcription by promoting CBP-mediated H2B acetylation. Nat Struct Mol Biol 21:981-9