Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors

Clinical Epigenetics

James R Davie¹  Dilshad H Khan¹  Geneviève P Delcuve¹ 

[1] Manitoba Institute of Cell Biology, University of Manitoba, 675 McDermot Avenue, Winnipeg, MB, R3E 0V9, Canada

关键词: epigenetics;    noncoding RNAs;    gene expression;    HDAC complexes;    HDAC inhibitors;    HDAC;    histone deacetylase;   

Others  :  791454
DOI  :  10.1186/1868-7083-4-5

 received in 2012-01-25, accepted in 2012-03-12,  发布年份 2012

【 摘 要 】

The zinc-dependent mammalian histone deacetylase (HDAC) family comprises 11 enzymes, which have specific and critical functions in development and tissue homeostasis. Mounting evidence points to a link between misregulated HDAC activity and many oncologic and nononcologic diseases. Thus the development of HDAC inhibitors for therapeutic treatment garners a lot of interest from academic researchers and biotechnology entrepreneurs. Numerous studies of HDAC inhibitor specificities and molecular mechanisms of action are ongoing. In one of these studies, mass spectrometry was used to characterize the affinities and selectivities of HDAC inhibitors toward native HDAC multiprotein complexes in cell extracts. Such a novel approach reproduces in vivo molecular interactions more accurately than standard studies using purified proteins or protein domains as targets and could be very useful in the isolation of inhibitors with superior clinical efficacy and decreased toxicity compared to the ones presently tested or approved. HDAC inhibitor induced-transcriptional reprogramming, believed to contribute largely to their therapeutic benefits, is achieved through various and complex mechanisms not fully understood, including histone deacetylation, transcription factor or regulator (including HDAC1) deacetylation followed by chromatin remodeling and positive or negative outcome regarding transcription initiation. Although only a very low percentage of protein-coding genes are affected by the action of HDAC inhibitors, about 40% of noncoding microRNAs are upregulated or downregulated. Moreover, a whole new world of long noncoding RNAs is emerging, revealing a new class of potential targets for HDAC inhibition. HDAC inhibitors might also regulate transcription elongation and have been shown to impinge on alternative splicing.

【 授权许可】

   
2012 Delcuve et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

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