The nucleosome, composed of an octamer of highly conserved histone proteins and associated DNA, is the fundamental unit of eukaryotic chromatin. How arrays of nucleosomes are folded into higher-order structures, and how the dynamics of such compaction is regulated, are questions that remain largely unanswered. This proposal seeks to understand the role of core histone phosphorylation in regulating higher-order chromatin structure and altering """"""""epigenetic landscapes"""""""". More specifically, histone phosphorylation will be studied in the context of mitosis, apoptosis and DNA damage. One long-range objective of this proposal is to better understand the role that core histone phosphorylation plays in mediating """"""""cis"""""""" versus """"""""trans"""""""" mechanisms with an emphasis on effectors (""""""""readers"""""""") that engage phosphorylation modifications in a context-dependent fashion. A second long-range goal of this research program is to determine the enzyme systems responsible for adding (kinases or """"""""writers"""""""") or subtracting (phosphatases or """"""""erasers"""""""") these phosphorylation marks. We hypothesize that histone phosphorylation acts as molecular """"""""switches"""""""", or as part of potentially redundant, modification """"""""cassettes"""""""" to govern critical downstream chromatin associations with key effectors to determine compaction states. Understanding the physiological substrates and sites phosphorylated by these enzymes is of paramount importance. Just as studies on histone acetylation and methylation have led to a wealth of new insights into mechanisms of transcription, we anticipate that insights into histone phosphorylation will pave the way for a better understanding of chromosome condensation and DNA repair. To achieve these goals, we will employ complementary genetic, biochemical and immunocytochemical approaches in a variety of model systems. The highly conserved nature of histone proteins, as well as the phosphorylation events and the relevant enzyme systems involved, underscore the fundamental nature of the chromatin problem for all DNA-templated processes. The close association of histone kinases, such as aurora kinase, and specialized histone variants, such as H2A.X, with oncogenesis provides strong support for an emerging view that covalent modifications of histones plays a vital role in the regulation of chromatin dynamics with far-reaching implications for human biology and disease, notably cancer.

Public Health Relevance

Although every gene exists within every cell in the human body, only a small percentage of genes are active in any given cell type. Chromatin, DNA and associated histone proteins, is the physiological form of our genome. Dr. Allis and his colleagues favor the view that distinct patterns of covalent histone modifications (chemical groups such as phosphate) form a histone code that is then read by effector proteins to bring about distinct downstream events. Through such enzymatic processes, histones are believed to function like a master on/off switch to determine whether particular genes are active or inactive. Knowing how to control which genes to turn on or off, using therapy, could reduce the risk of certain diseases. The implications of this research for human biology and human health are far-reaching.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM040922-28
Application #
8393477
Study Section
Molecular Genetics C Study Section (MGC)
Program Officer
Carter, Anthony D
Project Start
1990-07-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
28
Fiscal Year
2013
Total Cost
$501,387
Indirect Cost
$204,708
Name
Rockefeller University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Sabari, Benjamin R; Zhang, Di; Allis, C David et al. (2017) Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol 18:90-101
Josefowicz, Steven Z; Shimada, Miho; Armache, Anja et al. (2016) Chromatin Kinases Act on Transcription Factors and Histone Tails in Regulation of Inducible Transcription. Mol Cell 64:347-361
Noh, Kyung-Min; Allis, C David; Li, Haitao (2016) Reading between the Lines: ""ADD""-ing Histone and DNA Methylation Marks toward a New Epigenetic ""Sum"". ACS Chem Biol 11:554-63
Allis, C David; Jenuwein, Thomas (2016) The molecular hallmarks of epigenetic control. Nat Rev Genet 17:487-500
Li, Yuanyuan; Sabari, Benjamin R; Panchenko, Tatyana et al. (2016) Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain. Mol Cell 62:181-93
Xiong, Xiaozhe; Panchenko, Tatyana; Yang, Shuang et al. (2016) Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat Chem Biol 12:1111-1118
Soshnev, Alexey A; Josefowicz, Steven Z; Allis, C David (2016) Greater Than the Sum of Parts: Complexity of the Dynamic Epigenome. Mol Cell 62:681-94
Sabari, Benjamin R; Tang, Zhanyun; Huang, He et al. (2015) Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol Cell 58:203-15
Korb, Erica; Herre, Margo; Zucker-Scharff, Ilana et al. (2015) BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice. Nat Neurosci 18:1464-73
Rothbart, Scott B; Dickson, Bradley M; Raab, Jesse R et al. (2015) An Interactive Database for the Assessment of Histone Antibody Specificity. Mol Cell 59:502-11

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