α Actinin 4 potentiates MEF2 transcription activity by antagonizing HDAC7

Histone deacetylase 7 (HDAC7) is a member of class IIa HDACs that regulate MEF2‐mediated transcription and participate in multiple cellular processes. We have identified alpha actinin 1 and 4 as class IIa HDAC interacting proteins. The interaction domains are mapped to C‐terminus of á actinin 4 and amino acids 72–172 of HDAC7. A point mutation in HDAC7 that disrupts its association with MEF2A also disrupts its association with á actinin 4, indicating that MEF2A and á actinin 4 binding sites are largely overlapping. We have also isolated a novel splice variant of á actinin 4 that is predominantly localized in the nucleus, a pattern distinct from the full‐length á actinin 4, which is primarily distributed in the cytoplasm and plasma membrane. Using siRNA, ChIP, and transient transfection assays, we show that á actinin 4 potentiates expression of TAF55, a MEF2 target gene. Loss of MEF2A interaction correlates with loss of the ability of á actinin 4 to potentiate TAF55 promoter activity. Ectopic expression of á actinin 4, but not the mutant defective in MEF2A association, leads to disruption of HDAC7:MEF2A association and enhancement of MEF2‐mediated transcription. Taken together, we have identified a novel mechanism by which HDAC7 activity is negatively regulated and uncovered a previously unknown function of á actinin 4.