Genomic DNA of a human cell is packaged in 23 pairs of chromosomes that are collectively called chromatin. Chromatin is not a storage space. Rather it functions as a fundamental regulator that governs global dynamic changes of gene expression. Site-specific modifications of histones - the DNA packing proteins in chromatin - play an essential role in controlling of the capacity of the human genome to store, release and inherit biological information. Studies of histone modifications previously led to the formation of the histone code hypothesis stating that patterns of histone modifications constitute a code that specifies transcriptional outcomes. While this hypothesis has played an important role in propelling the chromatin biology field in the past decade, mounting evidence argues that histone modifications exert context-dependent functions rather than a code. However, we still have very limited knowledge of how histone modifications work in concert to direct gene expression. The goal of our research in epigenetics is to understand how chromatin modifications lead to regulatory capability of chromatin that directs both gene silencing and "on demand" expression in an orderly manner. Over the past years, we have elucidated the structure and mechanism of histone modifying enzymes and histone binding protein domains. Built on the lessons learned from our own studies, as well as from those of other leading research labs in the field, we postulate that gene expression (or silencing) in chromatin proceeds with an instruction that is programmed with a set of molecular activities of the conserved functional units that are present in participating proteins, and that these basic molecular functions including chromatin modifying activities and modification-directed molecular interactions constitute alphabets of a chromatin language of gene expression. In this project, we will test and develop mechanistic models predicted by this hypothesis through the study of the structure and mechanism of tandem chromatin protein modules in the functional context of gene transcription. To tackle this highly dynamic and complex biological system, we use an integrated structural/chromatin biology approach.
The specific aims of this project are to: (1) characterize the basic mechanisms of acetylated and methylated histone recognition in gene expression;(2) investigate molecular interplay of different histone modifications;and (3) define the histone crosstalk by the tandem chromatin modules in gene transcription.

Public Health Relevance

Site-specific histone modifications determine transcriptional activation or silencing of human genes. While important histone modifying enzymes have been identified, it remains elusive as to how these epigenetic chromatin modifications work in concert to control gene expression. To address this scientific challenge, we will perform structural and functional characterization of the conserved tandem protein modules as part of a chromatin language of gene expression hypothesis, the results of which will have important implications in a better understanding of epigenetic mechanisms underlying gene transcription in a chromatin context in human biology of health and disease, particularly cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087658-13
Application #
8629700
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Knowlton, John R
Project Start
2000-07-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
13
Fiscal Year
2014
Total Cost
$280,677
Indirect Cost
$114,532
Name
Icahn School of Medicine at Mount Sinai
Department
Pharmacology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Gacias, Mar; Gerona-Navarro, Guillermo; Plotnikov, Alexander N et al. (2014) Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem Biol 21:841-54
Zeng, Lei; Kuti, Miklos; Mujtaba, Shiraz et al. (2014) Structural insights into FRS2? PTB domain recognition by neurotrophin receptor TrkB. Proteins 82:1534-41
Plotnikov, Alexander N; Yang, Shuai; Zhou, Thomas Jiachi et al. (2014) Structural insights into acetylated-histone H4 recognition by the bromodomain-PHD finger module of human transcriptional coactivator CBP. Structure 22:353-60
Meslamani, Jamel; Smith, Steven G; Sanchez, Roberto et al. (2014) ChEpiMod: a knowledgebase for chemical modulators of epigenome reader domains. Bioinformatics 30:1481-3
Sanchez, Roberto; Meslamani, Jamel; Zhou, Ming-Ming (2014) The bromodomain: from epigenome reader to druggable target. Biochim Biophys Acta 1839:676-85
Shi, Jian; Wang, Yifan; Zeng, Lei et al. (2014) Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer. Cancer Cell 25:210-25
Di Micco, Raffaella; Fontanals-Cirera, Barbara; Low, Vivien et al. (2014) Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep 9:234-47
Marmorstein, Ronen; Zhou, Ming-Ming (2014) Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol 6:a018762
Charlop-Powers, Zachary; Jakoncic, Jean; Gurnon, James R et al. (2012) Paramecium bursaria chlorella virus 1 encodes a polyamine acetyltransferase. J Biol Chem 287:9547-51
Yap, Kyoko L; Zhou, Ming-Ming (2011) Structure and mechanisms of lysine methylation recognition by the chromodomain in gene transcription. Biochemistry 50:1966-80

Showing the most recent 10 out of 27 publications