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Histone Deacetylases (HDACs)
Posted on: December 31, 2010

Transcriptional regulation in eukaryotes occurs within a chromatin setting, and is strongly influenced by the post-translational modification of histones, the building blocks of chromatin, such as methylation, phosphorylation and acetylation. Acetylation is probably the best understood of these modifications: hyperacetylation leads to an increase in the expression of particular genes, and hypoacetylation has the opposite effect.

Many studies have identified several large, multisubunit enzyme complexes that are responsible for the targeted deacetylation of histones. SAGE (serial analysis of gene expression) data show that HDACs are generally expressed in almost all tissues investigated. Surprisingly, no major differences were observed between the expression pattern in normal and malignant tissues. However, significant variation in HDAC expression was observed within tissue types. HDAC inhibitors have been shown to induce specific changes in gene expression and to influence a variety of other processes, including growth arrest, differentiation, cytotoxicity and induction of apoptosis.

This challenging field has generated many fascinating results, which will ultimately lead to a better understanding of the mechanism of gene transcription as a whole. To analyze mechanisms of senescence-associated gene expression, histone deacetylases (HDACs) in human fibroblasts undergoing replicative senescence have been investigated. It was found that the overall acetylation pattern of histones does not vary detectably with replicative senescence. By Northern blot and Western blot, a significant decrease in the abundance of HDAC-1 in senescent cells was found.

Biochemical analysis of deacetylase activities in extracts from old and young cells revealed a striking difference. While by anion exchange chromatography a single peak of activity in extracts from young cells, which coincided with the elution of both HDAC-1 and HDAC-2, in senescent cells a second peak of activity was found. This second peak of activity is associated with HDAC-2 but does not contain HDAC-1. These results suggest that HDAC-2 is present in at least two distinct forms, one of which is specific for senescent cells.

Further biochemical characterization of the enzyme activity revealed that addition of nicotinamide adenine dinucleotide (NAD) did not detectably influence the activity of any fraction, suggesting that NAD is not an essential co-factor for the analyzed HDACs from diploid human fibroblasts.

In another study, decreased expression of histone deacetylases (HDACs), followed by downregulation of polycomb group genes (PcGs), such as BMI1, EZH2 and SUZ12, and by upregulation of jumonji domain containing 3 (JMJD3), was observed in senescent MSCs. Similarly, HDAC inhibitors induced cellular senescence through downregulation of PcGs and upregulation of JMJD3. Regulation of PcGs was associated with HDAC inhibitor-induced hypophosphorylation of RB, which causes RB to bind to and decrease the transcriptional activity of E2F. JMJD3 expression regulation was dependant on histone acetylation status at its promoter regions. A histone acetyltransferase (HAT) inhibitor prevented replicative senescence of MSCs.

These results suggest that HDAC activity might be important for MSC self-renewal by balancing PcGs and JMJD3 expression, which govern cellular senescence by p16(INK4A) regulation.

1. Annemieke J. M et al.; Histone deacetylases (HDACs): characterization of the classical HDAC family; Biochem. J. (2003) 370, 737-749;
2. M. Wagner, G. Brosch, W. Zwerschke, E. Seto, P. Loidl, P. Jansen-Durr; Histone deacetylases in replicative senescence: evidence for a senescence-specific form of HDAC-2; FEBS Letters 499 (2001) 101-106;
3. Ji-Won Jung, Seunghee Lee, Min-Soo Seo, Sang-Bum Park, Andreas Kurtz, Soo-Kyung Kang, Kyung-Sun Kang; Histone deacetylase controls adult stem cell aging by balancing the expression of polycomb genes and jumonji domain containing 3; Cell. Mol. Life Sci. (2010) 67:1165-1176 DOI 10.1007/s00018-009-0242-9.
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