Regulation of MEF2 by Histone Deacetylase 4- and SIRT1 Deacetylase-Mediated Lysine Modifications

Abstract

The class II deacetylase histone deacetylase 4 (HDAC4) negatively regulates the transcription factor MEF2. HDAC4 is believed to repress MEF2 transcriptional activity by binding to MEF2 and catalyzing local histone deacetylation. Here we report that HDAC4 also controls MEF2 by a novel SUMO E3 ligase activity. We show that HDAC4 interacts with the SUMO E2 conjugating enzyme Ubc9 and is itself sumoylated. The overexpression of HDAC4 leads to prominent MEF2 sumoylation in vivo, whereas recombinant HDAC4 stimulates MEF2 sumoylation in a reconstituted system in vitro. Importantly, HDAC4 promotes sumoylation on a lysine residue that is also subject to acetylation by a MEF2 coactivator, the acetyltransferase CBP, suggesting a possible interplay between acetylation and sumoylation in regulating MEF2 activity. Indeed, MEF2 acetylation is correlated with MEF2 activation and dynamically induced upon muscle cell differentiation, while sumoylation inhibits MEF2 transcriptional activity. Unexpectedly, we found that HDAC4 does not function as a MEF2 deacetylase. Instead, the NAD ؉ -dependent deacetylase SIRT1 can potently induce MEF2 deacetylation. Our studies reveal a novel regulation of MEF2 transcriptional activity by two distinct classes of deacetylases that affect MEF2 sumoylation and acetylation.Precise temporal and spatial gene expression is critical for the execution of the differentiation program and other important biological processes. This tight regulation of gene expression is achieved by the interplay of transcriptional activation and repression controlled by transcription factors that recruit specific cofactor complexes capable of modifying histones and the local chromatin structure (reviewed in references 12 and 29). Among the cofactors that are involved in transcriptional repression, members of the histone deacetylase (HDAC) family are the most well characterized. Numerous studies have reported the recruitment of HDAC members by transcription factors to repress gene expression. Based on the long-established correlation between histone acetylation and gene transcription, it is generally thought that HDAC members repress gene transcription by catalyzing local histone deacetylation (reviewed in reference 21). However, whether this mechanism is universally applicable to HDAC-mediated transcriptional repression is not known.Among HDAC family members involved in transcriptional regulation, HDAC4 and HDAC5 are closely related and belong to a subfamily that also includes HDAC7 and HDAC9 (reviewed in reference 37). This subfamily of HDACs share several unique properties. First, they all contain the N-terminal noncatalytic MITR (MEF2-interacting transcription repressor) homology domain (37). Second, they are all regulated by phosphorylation-dependent cytoplasmic-nuclear trafficking (18,23,45). Third, and most importantly, they are all critical regulators of MEF2, a family of transcription factors important in muscle cell differentiation and apoptosis (reviewed in reference 24). In skeletal muscle cells, MEF2 members coll...

Class IIa histone deacetylases: regulating the regulators

“…Therefore, in addition to the HDAC activity associated with their C terminus, class IIa HDACs might also repress MEF2 transcriptional activity through association of their N-terminal domain with corepressors such as HP1 or CtBP (Zhang et al, , b, 2002a. Recently, HDAC4 and -5 were shown to promote sumoylation of MEF2, which results in inhibition of its transcriptional activity Zhao et al, 2005;Gregoire et al, 2006). As opposed to the original model, these results illustrate the multiple levels of regulation of MEF2 by class IIa HDACs and emphasize the need for further work to achieve comprehensive understanding of these mechanisms (Figure 2).…”

“…As SUMO E3 ligases In addition to being sumoylated, HDAC4, and potentially other class IIa members can act as small ubiquitin-like modifier (SUMO) E3 ligases, a property dependent on their N-terminal domain Zhao et al, 2005;Gregoire et al, 2006). Interestingly, MEF2 was identified as a relevant target for this novel class IIa-associated enzymatic activity.…”

Myocyte Enhancer Factor 2A Is Transcriptionally Autoregulated

“…These associate with MEF2 proteins and influence chromatin structure to inactivate target gene expression (29,60). Transrepression is also produced by an independent but uncharacterized mechanism associated with the modification of a MEF2 ␥ domain Lys residue, ␥ K , by small ubiquitin-like modifiers (SUMO) (18,26,27,63). The mode by which the MEF2 element silences MEF2A promoter 1 may entail one or both of these processes.…”

SIRT1 stabilizes PML promoting its sumoylation

“…39,40 In addition, class IIa HDACs -HDAC4, HDAC5, and HDAC7 -increase PML sumoylation in an acetylationindependent manner, 41 and although it is not clear exactly how HDAC4 and related members positively regulate the sumoylation levels of PML, a putative SUMO E3 ligase activity has been suggested. 42 PML has an inhibitory effect on virus infections in vitro and in vivo. 5 Thus, overexpression of PML confers resistance against VSV, influenza virus, human foamy virus (HFV), and lymphocytic choriomeningitis virus (LMCV).…”