Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases

Abstract

Myocyte enhancer factor-2 (MEF2) transcription factors control muscle-specific and growth factor-inducible genes. We show that hypertrophic growth of cardiomyocytes in response to phenylephrine and serum is accompanied by activation of MEF2 through a posttranslational mechanism mediated by calcium, calmodulindependent protein kinase (CaMK), and mitogen-activated protein kinase (MAPK) signaling. CaMK stimulates MEF2 activity by dissociating class II histone deacetylases (HDACs) from the DNA-binding domain. MAPKs, which activate MEF2 by phosphorylation of the transcription activation domain, maximally stimulate MEF2 activity only when repression by HDACs is relieved by CaMK signaling to the DNA-binding domain. These findings identify MEF2 as an endpoint for hypertrophic stimuli in cardiomyocytes and demonstrate that MEF2 mediates synergistic transcriptional responses to the CaMK and MAPK signaling pathways by signal-dependent dissociation from HDACs.M yocyte enhancer factor-2 (MEF2) transcription factors (1) participate in diverse gene regulatory programs, including those for muscle and neural differentiation, cardiac morphogenesis, blood vessel formation, and growth factor responsiveness (reviewed in ref.2). The four MEF2 factors, MEF2A, -B, -C, and -D, share high homology in an amino-terminal MADS (MCMI, Agamous, Deficiens, Serum response factor) domain that mediates DNA-binding and dimerization and an adjacent MEF2-specific domain that influences DNA-binding affinity and interaction with transcriptional cofactors (2). The carboxyl-terminal regions of MEF2 factors, which are more divergent, act as transcription activation domains (TADs).Studies in T cells and fibroblasts have shown that the mitogenactivated protein kinases (MAPKs) p38 and ERK5 stimulate transcriptional activity of MEF2 factors by phosphorylating conserved sites in their TADs (3-12). Calcium, calmodulindependent protein kinase (CaMK), and calcineurin also stimulate MEF2 activity (13,14), but the underlying mechanisms are unknown. It is also unclear whether MAPK, CaMK, and calcineurin pathways cross-talk or act in parallel to activate MEF2.Most studies of MEF2 activation by extracellular signaling have focused on cells that are highly responsive to mitogens. Whether MEF2 retains the ability to respond to growth factor signals in terminally differentiated muscle cells, which are permanently postmitotic, and whether MEF2 is activated in muscle cells by the same signaling pathways as in other cell types has not been determined. In cardiac myocytes, growth factor signals evoke a hypertrophic response characterized by cell enlargement, activation of immediate early genes, reactivation of fetal cardiac muscle genes, and sarcomere assembly (reviewed in ref. 15).To investigate the mechanisms that regulate MEF2 activity in response to extracellular signals and to test whether MEF2 retains its ability to respond to growth factor signals in terminally differentiated muscle cells, we sought to determine whether MEF2 could be activated by hypertrophic signals ...

Calcium/Calmodulin-dependent Protein Kinase Activates Serum Response Factor Transcription Activity by Its Dissociation from Histone Deacetylase, HDAC4

“…Earlier reports have suggested that Ca 2ϩ /CaMK signaling is a common mechanism to relieve transcriptional repression imposed by interactions of HDACs with transcription factors. For instance, the MEF2/HDAC4/5 interaction was also shown to be disrupted by increased levels of Ca 2ϩ and CaMK-dependent phosphorylation, resulting in cytoplasmic relocation of the HDAC⅐14-3-3 complex and derepression of the transcription activity of MEF2 (30,43). Since multiple Ca 2ϩ -dependent pathways are known to be involved during hypertrophic response of cardiac myocytes, it remains to be determined which is the rate-limiting pathway contributing to the association/localization of HDAC4⅐SRF complex and subsequent activation of SRF-dependent cardiac muscle gene expression.…”

Class II histone deacetylases: versatile regulators

“…Class IIa HDACs inhibit myogenesis by binding to MEF2 at several promoters critical for the muscle differentiation program (for recent reviews see Refs [63,64]). HDAC4, -5, -7 and -9 interact with MEF2 proteins through a highly conserved 17 amino acid motif located in their N-termini [7,23,38,65,66].…”

“…Expression of an HDAC -VP16 fusion protein, in which the VP16 activation domain replaces the catalytic domain of HDAC4 or -5, enhances myogenic conversion [47]. Activation of the CaMK signaling pathway also overcomes the HDAC-mediated repression of muscle-specific gene expression and induces the myogenic conversion program [22,64]. Further evidence for the role of class IIa HDACs in cardiac and skeletal myogenesis comes from the phenotype of HDAC9-deficient animals.…”

Caspase-mediated Specific Cleavage of Human Histone Deacetylase 4

“…HDAC4 has been linked to the transcriptional repression, including its effects on the MEF2 family of transcription factors (27)(28)(29)(30). HDAC4 binds directly to MEF2 and has been identified as a component of corepressor complexes (31)(32)(33)(34).…”