Calcium/calmodulin-dependent protein kinase activates serum response factor transcription activity by its dissociation from histone deacetylase, HDAC4 - Implications in cardiac muscle gene regulation during hypertrophy

Serum response factor (SRF) plays a pivotal role in cardiac myocyte development, muscle gene transcription, and hypertrophy. Previously, elevation of intracellular levels of Ca2+ was shown to activate SRF function without involving the Ets family of tertiary complex factors through an unknown regulatory mechanism. Here, we tested the hypothesis that the chromatin remodeling enzymes of class II histone deacetylases (HDAC4) regulate SRF activity in a Ca2+-sensitive manner. Expression of HDAC4 profoundly repressed SRF-mediated transcription in both muscle and nonmuscle cells. Protein interaction studies demonstrated physical association of HDAC4 with SRF in living cells. The SRF/HDAC4 co-association was disrupted by treatment of cells with hypertrophic agonists such as angiotensin-II and a Ca2+ ionophore, ionomycin. Furthermore, activation of Ca2+/calmodulin-dependent protein kinase (CaMK)-IV prevented SRF/HDAC4 interaction and derepressed SRF-dependent transcription activity. The SRF.HDAC4 complex was localized to the cell nucleus, and the activated CaMK-IV disrupted HDAC4/SRF association, leading to export of HDAC4 from the nucleus and stimulation of SRF transcription activity. Thus, these results identify SRF as a functional interacting target of HDAC4 and define a novel tertiary complex factor-independent mechanism for SRF activation by Ca2+/CaMK-mediated signaling.