Histone post-translational modifications are critical for establishing chromatin environments that facilitate or inhibit gene expression. Such organization is especially important during developmental processes, as failure to activate or repress lineage specific expression programs leads to embryonic defects and often death (11, 12). Histone acetylation is a key regulator of chromatin accessibility, but we still have much to learn about the roles of specific HATs or HDACS in developmental or disease processes. Our lab has used genetic approaches in mice and in ES cells to define the functions of Gcn5, the first transcription-related HAT to be identified (1). Our previous studies demonstrated that Gcn5 is essential for normal mouse development (5, 6). We also discovered that deletion of Gcn5 leads to loss of a deubiquitylase (DUB) module from the Gcn5- containing SAGA complex and that this module has an unexpected role in telomere maintenance (7). Additional studies in mouse embryonic stem (ES) cells revealed that Gcn5 is an important co-activator for Myc and E2F1 in the regulation of a self-renewal network in ES cells and in reprogramming of somatic cells to a stem cell state (Hirsch et al, submitted). We hypothesize that Gcn5 also regulates critical gene expression programs during development, as reflected by the severity of the phenotypes of Gcn5 mutant embryos.
In Aim 1 of this proposal, we propose both genomic and single cell level experiments to define developmental programs that require Gcn5 during ES cell differentiation in vitro.
In Aim 2, we propose genome editing approaches to define the functions of a highly conserved bromodomain in Gcn5, which likely serves to promote Gcn5 interactions with acetylated lysines in histones and other proteins important for normal development. Large-scale cancer genomic analyses indicate that Gcn5 is overexpressed in a number of cancers (The Cancer Genome Atlas). Specific SAGA components are also linked to SCA7, a debilitating neurodegenerative disease (9, 10). In the longer term, our definition of the functions of Gcn5 during development will provide new insights into how Gcn5 and SAGA contribute to oncogenesis and neurodegeneration, as well as new therapeutic options for these conditions.

Public Health Relevance

The packaging of the genome inside the cell nucleus controls the growth, identity and behavior of the cell, and mistakes in this packaging contribute to human disease. Our studies aim to define the functions of Gcn5, an enzyme that regulates genomic packaging, during mouse development. These studies will help us understand how aberrant expression of Gcn5 and associated proteins contributes to cancer and to neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067718-11
Application #
9251293
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Carter, Anthony D
Project Start
2003-05-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
11
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Overall Medical
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Hirsch, Calley L; Wrana, Jeffrey L; Dent, Sharon Y R (2017) KATapulting toward Pluripotency and Cancer. J Mol Biol 429:1958-1977
Wang, Yajun; Yun, Chawon; Gao, Beixue et al. (2017) The Lysine Acetyltransferase GCN5 Is Required for iNKT Cell Development through EGR2 Acetylation. Cell Rep 20:600-612
Mi, Wenyi; Guan, Haipeng; Lyu, Jie et al. (2017) YEATS2 links histone acetylation to tumorigenesis of non-small cell lung cancer. Nat Commun 8:1088
Gao, Beixue; Kong, Qingfei; Zhang, Yana et al. (2017) The Histone Acetyltransferase Gcn5 Positively Regulates T Cell Activation. J Immunol 198:3927-3938
Hirsch, Calley L; Coban Akdemir, Zeynep; Wang, Li et al. (2015) Myc and SAGA rewire an alternative splicing network during early somatic cell reprogramming. Genes Dev 29:803-16
Farria, A; Li, W; Dent, S Y R (2015) KATs in cancer: functions and therapies. Oncogene 34:4901-13
Wang, Li; Dent, Sharon Y R (2014) Functions of SAGA in development and disease. Epigenomics 6:329-39
Li, Yuanyuan; Wen, Hong; Xi, Yuanxin et al. (2014) AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell 159:558-71
Chen, Taiping; Dent, Sharon Y R (2014) Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat Rev Genet 15:93-106
Jin, Qihuang; Zhuang, Lenan; Lai, Binbin et al. (2014) Gcn5 and PCAF negatively regulate interferon-? production through HAT-independent inhibition of TBK1. EMBO Rep 15:1192-201

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