Despite the phenomenal increase in the identification of genes and gene products of the human genome from the human genome sequencing, major challenges remain in the understanding of regulation and transduction of genetic information. Mounting evidence shows that site-specific post-translational modifications of histones - the main protein component of chromatin - play an important role in controlling of the capacity of the eukaryotic genome to store, release and inherit biological information. Such studies of histone modifications led to the histone code hypothesis, which predicts that """"""""multiple histone modifications, acting in a combinatorial or sequential fashion on one or multiple histone tails, specify unique downstream functions"""""""". The models for the sequential readout of the histone code are supported by several findings, including our own discovery that bromodoains function as histone acetyl- lysine binding domains. However, the prediction for combinatorial readout of the histone code currently lacks evidence. In this Project, we aim to develop an integrated structure-guided paradigm in order to define fundamental principles that dictate histone-directed chromatin function. Through systematic characterization of the structure-function relationships of conserved modular domains present in many chromatin and transcription proteins, we aim to test and develop new mechanistic models that constitute sequential and combinatorial readout of the histone code in epigenetic control of gene expression and silencing. To attain this goal, our Specific Aims are: (1) to determine ligand binding selectivity of bromodomains;(2) to define the histone binding activity of the tandem bromodomain and PHD finger modules;and (3) to define combinatorial readout of the histone code by tandem chromatin protein modules. We expect that this new strategy of structure-based functional profiling of the evolutionary conserved protein domains, as being developed and enriched through the planned studies in this Project, may be generalizable to gain new mechanistic understanding of the fundamental and complex cellular functions of domain-bearing proteins and protein complexes in a wide array of cellular processes with far-reaching implications for human biology and disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087658-10
Application #
7776927
Study Section
Macromolecular Structure and Function B Study Section (MSFB)
Program Officer
Knowlton, John R
Project Start
2000-07-01
Project End
2012-04-30
Budget Start
2010-03-01
Budget End
2012-04-30
Support Year
10
Fiscal Year
2010
Total Cost
$290,327
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Physiology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Zhang, Qiang; Zeng, Lei; Zhao, Chengcheng et al. (2016) Structural Insights into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain. Structure 24:1606-12
Aguilo, Francesca; Li, SiDe; Balasubramaniyan, Natarajan et al. (2016) Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α. Cell Rep 14:479-92
Zhang, Qiang; Zeng, Lei; Shen, Chen et al. (2016) Structural Mechanism of Transcriptional Regulator NSD3 Recognition by the ET Domain of BRD4. Structure 24:1201-8
Ren, Chunyan; Morohashi, Keita; Plotnikov, Alexander N et al. (2015) Small-molecule modulators of methyl-lysine binding for the CBX7 chromodomain. Chem Biol 22:161-8
Rahman, Mohummad Aminur; Kristiansen, Per E; Veiseth, Silje V et al. (2014) The arabidopsis histone methyltransferase SUVR4 binds ubiquitin via a domain with a four-helix bundle structure. Biochemistry 53:2091-100
Marmorstein, Ronen; Zhou, Ming-Ming (2014) Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol 6:a018762
Smith, Steven G; Sanchez, Roberto; Zhou, Ming-Ming (2014) Privileged diazepine compounds and their emergence as bromodomain inhibitors. Chem Biol 21:573-83
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
Liu, Ruijie; Zhong, Yifei; Li, Xuezhu et al. (2014) Role of transcription factor acetylation in diabetic kidney disease. Diabetes 63:2440-53
Zeng, Lei; Kuti, Miklos; Mujtaba, Shiraz et al. (2014) Structural insights into FRS2α PTB domain recognition by neurotrophin receptor TrkB. Proteins 82:1534-41

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