Abstract
Precise control of SMC transcription plays a major role in vascular development
and pathophysiology. Serum response factor (SRF) controls SMC gene transcription
via binding to CArG box DNA sequences found within genes that exhibit
SMC-restricted expression. However, the mechanisms that regulate SRF association
with CArG box DNA within native chromatin of these genes are unknown. Here we
report that SMC-restricted binding of SRF to murine SMC gene CArG box chromatin
is associated with patterns of posttranslational histone modifications within
this chromatin that are specific to the SMC lineage in culture and in vivo,
including methylation and acetylation to histone H3 and H4 residues. We found
that the promyogenic SRF coactivator myocardin increased SRF association with
methylated histones and CArG box chromatin during activation of SMC gene
expression. In contrast, the myogenic repressor Kruppel-like factor 4 recruited
histone H4 deacetylase activity to SMC genes and blocked SRF association with
methylated histones and CArG box chromatin during repression of SMC gene
expression. Finally, we observed deacetylation of histone H4 coupled with loss
of SRF binding during suppression of SMC differentiation in response to vascular
injury. Taken together, these findings provide novel evidence that SMC-selective
epigenetic control of SRF binding to chromatin plays a key role in regulation of
SMC gene expression in response to pathophysiological stimuli in vivo.
