When DNA is replicated, the chromatin structure must be duplicated, as well. The pre-existing (or parental) histones are recycled and then reassembled following the passage of the replication near their original site of residence. Hence, the epigenetic inheritance of a specific chromatin domain can be facilitated by the spatial retention of the correctly modified parental histones. However, packaging of the newly replicated DNA requires the incorporation of an equal quantity of newly synthesized histones. This complicates the situation as, rather than being a blank slate upon which these specific patterns of modification can be reproduced, the newly synthesized histones are assembled with precise patterns of modification. The goal of this proposal is to understand the function of the histone acetyltransferase Hat1, which is necessary for the acetylation of newly synthesized histones. This proposal will focus on the function of Hat1 in the assembly and regulation of chromatin structure, as well as other aspects of cell metabolism. The first specific aim will use a variety of in vitro analyses to examine the mechanisms by which Hat1 influences the modification of newly synthesized histones and replication-coupled chromatin assembly. Hat1- containing complexes have both histone acetyltransferase and histone chaperone activities. One sub-aim will generate Hat1 mutations that specifically block each of these activities to identify the functions of Hat1 that are important for the processing of newly synthesized H3 and H4. A second sub-aim will employ affinity purification of newly replicated DNA to identify Hat1-dependent changes in nascent chromatin. The goal of the second aim of this proposal is to determine the role of Hat1 in mitochondrial function. Protein acetylation is known to play a critical role in the regulation of mitochondrial activity. However, the protein acetyltransferases responsible for the acetylation of mitochondrial proteins are completely unknown. We have found that Hat1 is localized to mitochondria and the goal of this aim is to identify substrates of hat1 in this organelle and determine how Hat1-dependent mitochondrial acetylation affects the function of this organelle.

Public Health Relevance

Many diseases are the result of uncontrolled or inappropriate cell proliferation. An important mechanism for controlling cell proliferation is proper epigenetic inheritance. A key aspect of epigenetic inheritance is the duplication of the chromatin structure following DNA replication. This proposal focuses on a class of enzymes known as type B histone acetyltransferases that modify newly synthesized histones that are used to package newly replicated DNA. This proposal has two main areas of emphasis. First, we will address how the modification of newly synthesized histones influences chromatin assembly and epigenetic inheritance. Second, we will explore the surprising observation that a specific type B histone acetyltransferase, Hat1, functions to modify proteins in the mitochondria.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM062970-17
Application #
9453688
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Carter, Anthony D
Project Start
2001-07-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
17
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Agudelo Garcia, Paula A; Hoover, Michael E; Zhang, Pei et al. (2017) Identification of multiple roles for histone acetyltransferase 1 in replication-coupled chromatin assembly. Nucleic Acids Res 45:9319-9335
Zhang, Pei; Branson, Owen E; Freitas, Michael A et al. (2016) Identification of replication-dependent and replication-independent linker histone complexes: Tpr specifically promotes replication-dependent linker histone stability. BMC Biochem 17:18
Bernier, Morgan; Luo, Yi; Nwokelo, Kingsley C et al. (2015) Linker histone H1 and H3K56 acetylation are antagonistic regulators of nucleosome dynamics. Nat Commun 6:10152
Singh, Rajbir; Harshman, Sean W; Ruppert, Amy S et al. (2015) Proteomic profiling identifies specific histone species associated with leukemic and cancer cells. Clin Proteomics 12:22
Renusch, Samantha R; Harshman, Sean; Pi, Hongyang et al. (2015) Spinal Muscular Atrophy Biomarker Measurements from Blood Samples in a Clinical Trial of Valproic Acid in Ambulatory Adults. J Neuromuscul Dis 2:119-130
Li, Yang; Zhang, Li; Liu, Tingting et al. (2014) Hat2p recognizes the histone H3 tail to specify the acetylation of the newly synthesized H3/H4 heterodimer by the Hat1p/Hat2p complex. Genes Dev 28:1217-27
Guan, Xiaoyan; Rastogi, Neha; Parthun, Mark R et al. (2014) SILAC peptide ratio calculator: a tool for SILAC quantitation of peptides and post-translational modifications. J Proteome Res 13:506-16
Knapp, Amy R; Wang, Huanyu; Parthun, Mark R (2014) The yeast histone chaperone hif1p functions with RNA in nucleosome assembly. PLoS One 9:e100299
Ge, Zhongqi; Nair, Devi; Guan, Xiaoyan et al. (2013) Sites of acetylation on newly synthesized histone H4 are required for chromatin assembly and DNA damage response signaling. Mol Cell Biol 33:3286-98
Nagarajan, Prabakaran; Ge, Zhongqi; Sirbu, Bianca et al. (2013) Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4. PLoS Genet 9:e1003518

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