Disrupting the reader of histone language.
Disrupting the reader of histone language.
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DOI：
10.1002/anie.201101414
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发表时间：
2011-06-20
影响因子：
16.6
通讯作者：
Denu, John M.
中科院分区：
文献类型：
--
作者：
Oliver, Samuel S.;Denu, John M.
Research in chromatin and epigenetics is rapidly expanding, and with this growth comes opportunities for the development of novel therapeutics that target newly identified players. Although the human genome is a blueprint of cellular potential, an additional layer of information, the epigenome, ultimately controls whether particular genes are expressed in their appropriate context [1a, b]. The epigenome consists of a complex array of specific chemical ‘marks’ on chromatin (the DNA-protein complex), which can dynamically regulate gene expression [1b]. These chromatin-based mechanisms are being revealed and recent evidence suggests that targeting these pathways holds great promise for therapeutic interventions of human disease and afflictions.Chromatin consists of histone proteins (core histones H2A, H2B, H3 and linker histones) that spool DNA and can restrict access to protein machines that transcribe the DNA sequence into functional gene products [2a, b]. Post-translational modifications (PTMs)(eg phosphorylation, acetylation and methylation) on histones regulate the accessibility of DNA through a number of mechanisms. The combination of PTMs in the proper context is thought to give rise to a ‘histone code’or ‘histone language’that is read and interpreted by an array of diverse proteins [3a, b]. These proteins can be divided into three broad classes of ‘writers’,‘erasers’, or ‘readers’. The so-called ‘writers’ and ‘erasers’ of histone PTMs are enzymes such as acetyltransferases, deacetylases, kinases, phosphatases, methyltransferases and demethylases. Among the protein ‘readers’ of this histone language are the bromodomain family that function as acetyl-lysine recognition motifs [4a, b]. There are 57 bromodomains found among 41 different human proteins. The bromodomain and extraterminal (BET) subfamily are represented by BRD2, BRD3, BRD4 and BRDT [5]. The BET family of bromodomains share a similar domain architecture with two highly conserved amino-terminal bromodomains. Two recent studies report the development of smallmolecule compounds that specifically disrupt the interactions between these bromodomains and acetylated histone tails [6a, b]. These results provide compelling proof-of-concept that disrupting histone readers is a viable strategy for the development of epigenetic drugs.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Goldberg, Aaron D.;Allis, C. David;Bernstein, Emily
通讯作者：
Bernstein, Emily
影响因子：
3.2
作者：
Oliver, Samuel S.;Denu, John M.
通讯作者：
Denu, John M.
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
Luger, K;Mader, AW;Richmond, TJ
通讯作者：
Richmond, TJ