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Chemical approaches to understand the language of histone modifications.

ABSTRACT: Genomic DNA in the eukaryotic cell nucleus is present in the form of chromatin. Histones are the principal protein component of chromatin, and their post-translational modifications play important roles in regulating the structure and function of chromatin and thereby in determining cell development and disease. An understanding of how histone modifications translate into downstream cellular events is important from both developmental and therapeutic perspectives. However, biochemical studies of histone modifications require access to quantities of homogenously modified histones that cannot be easily isolated from natural sources or generated by enzymatic methods. In the past decade, chemical synthesis has proven to be a powerful tool in translating the language of histone modifications by providing access to uniformly modified histones and by the development of stable analogues of thermodynamically labile modifications. This Review highlights the various synthetic and semisynthetic strategies that have enabled biochemical and biophysical characterization of site-specifically modified histones.

SUBMITTER: Dhall A

PROVIDER: S-EPMC7020651 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Chemical approaches to understand the language of histone modifications.

Dhall Abhinav A Chatterjee Champak C

ACS chemical biology 20110817 10

Genomic DNA in the eukaryotic cell nucleus is present in the form of chromatin. Histones are the principal protein component of chromatin, and their post-translational modifications play important roles in regulating the structure and function of chromatin and thereby in determining cell development and disease. An understanding of how histone modifications translate into downstream cellular events is important from both developmental and therapeutic perspectives. However, biochemical studies of ...[more]

PMID: 21827195

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Project description: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 offer information otherwise difficult 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, chemical ligation, mass spectrometry, biochemical methylation and demethylation 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 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 applications in the clinic.

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Chemical approaches to understand the language of histone modifications.

Publications

Chemical approaches to understand the language of histone modifications.

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