Selective HAT Inhibitors as Mechanistic Tools for Protein Acetylation

Zheng, Y. George; Thompson, Paul R.; Cebrat, Marek; Wang, Ling; Devlin, Meghann K; Alani, Rhoda M.; Cole, Philip A.

doi:10.1016/s0076-6879(03)76012-1

Cited by 41 publications

(27 citation statements)

References 28 publications

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“…Linoleoyl-CoA, myristoyl-CoA, oleoyl-CoA, and palmitoleoyl-CoA were purchased from Sigma with purity verified by LC-MS prior to use. H3K14-CoA and desulfo-CoA were synthesized according to previously reported procedures (Chase et al, 1966; Montgomery et al, 2014; Zheng et al, 2004). Qubit Protein Assay kit (Life Technologies) was used to determine cell lysate and histone extract concentrations.…”

Section: Methodsmentioning

confidence: 99%

Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors

Montgomery

Sorum

Guasch

et al. 2015

Chemistry & Biology

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SUMMARY The finding that chromatin modifications are sensitive to changes in cellular cofactor levels potentially links altered tumor cell metabolism and gene expression. However, the specific enzymes and metabolites that connect these two processes remain obscure. Characterizing these metabolic-epigenetic axes is critical to understanding how metabolism supports signaling in cancer, and developing therapeutic strategies to disrupt this process. Here, we describe a chemical approach to define the metabolic regulation of lysine acetyltransferase (KAT) enzymes. Using a novel chemoproteomic probe, we identify a previously unreported interaction between fatty acyl-CoAs and KAT enzymes. Further analysis reveals that palmitoyl-CoA is a potent inhibitor of KAT activity and that fatty acyl-CoA precursors reduce cellular acetylation levels. These studies implicate fatty acyl-CoAs as endogenous regulators of histone acetylation, and suggest novel strategies for the investigation and metabolic modulation of epigenetic signaling.

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Section: Methodsmentioning

confidence: 99%

Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors

Montgomery

Sorum

Guasch

et al. 2015

Chemistry & Biology

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“…Autoradiograph was scanned on a Typhoon scanner and analyzed by QuantityOne software. Quantitation was accomplished according to 14 C-labeled BSA as standard. For the substrate histone H4 acetylation, a synthetic peptide corresponding to the first 20-amino acid sequence of the histone H4 N-terminal tail, i.e.…”

Section: Methodsmentioning

confidence: 99%

“…First discovered in nucleosomal histones, protein acetylation is now widely recognized extending far beyond the chromatin realm and orchestrates other diverse biological functions and processes, including cell cycle, cytoskeleton remodeling, chaperones, ribosome, and metabolic pathways (7)(8)(9)(10)(11)(12). In the past decade, significant progress has been made in various aspects of HAT biology, from enzyme kinetics, protein structures, gene regulation, signal transduction, and cell development to disease mechanism and inhibitor development (13)(14)(15)(16)(17)(18)(19). Based on the sequence and structural similarities, HATs are grouped into several major families, including GCN5/PCAF family, MYST family, p300/ CBP, and RTT109 (15,20,21).…”

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confidence: 99%

Autoacetylation of the MYST Lysine Acetyltransferase MOF Protein

Yang

Sinha

et al. 2012

Journal of Biological Chemistry

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“…Among different families of histone modifying enzymes, histone acetyltranfeases (HATs) are the best characterized to date. [21][22][23] While histone acetylation is generally correlated with increased chromatin accessibility and transcriptional activity, [24][25][26] the transcriptional impact of histone methylation depends on the specific contexts where the methylation mark is located. For example, methylation of histone H3 at lysine 4 is associated with actively transcribed genes, whereas H3 methylation at K9 is enriched at constitutively condensed chromatin and developmentally inactive global genes.…”

Section: Introductionmentioning

confidence: 99%

Chemical and biochemical approaches in the study of histone methylation and demethylation

Luo

Wang

et al. 2010

Med. Res. Rev.

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Histone methylation represents one of the most critical epigenetic events in DNA function regulation in eukaryotic organisms. Classic molecular biology and genetics tools provide significant knowledge about mechanisms and physiological roles of histone methyltransferases and demethylases in various cellular processes. In addition to this stream line, development and application of chemistry and chemistry-related techniques are increasingly involved in biological study, and provide information otherwise difficulty to obtain by standard molecular biology methods. Herein, we review recent achievements and progress in developing and applying chemical and biochemical approaches in the study of histone methylation, including chromatin immunoprecipitation (ChIP), chemical ligation, mass spectrometry (MS), biochemical assays, and inhibitor development. These technological advances allow histone methylation to be studied from genome-wide level to molecular and atomic levels. With ChIP technology, information can be obtained about precise mapping of histone methylation patterns at specific promoters, genes or other genomic regions. MS is particularly useful in detecting and analyzing methylation marks in histone and nonhistone protein substrates. Chemical approaches that permit site-specific incorporation of methyl groups into histone proteins greatly facilitate the investigation of the biological impacts of methylation at individual modification sites. Discovery and design of selective organic inhibitors of histone methyltransferases and demethylases provide chemical probes to interrogate methylation-mediated cellular pathways. Overall, these chemistry-related technological advances have greatly improved our understanding of the biological functions of histone methylation in normal physiology and diseased states, and also are of great potential to translate basic epigenetics research into diagnostic and therapeutic application in the clinic.

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Selective HAT Inhibitors as Mechanistic Tools for Protein Acetylation

Cited by 41 publications

References 28 publications

Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors

Metabolic Regulation of Histone Acetyltransferases by Endogenous Acyl-CoA Cofactors

Autoacetylation of the MYST Lysine Acetyltransferase MOF Protein

Chemical and biochemical approaches in the study of histone methylation and demethylation

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