Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo
Oliver G. McDonald, Brian R. Wamhoff, Mark H. Hoofnagle, Gary K. Owens
Oliver G. McDonald, Brian R. Wamhoff, Mark H. Hoofnagle, Gary K. Owens
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Research Article Genetics

Control of SRF binding to CArG box chromatin regulates smooth muscle gene expression in vivo

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.

Authors

Oliver G. McDonald, Brian R. Wamhoff, Mark H. Hoofnagle, Gary K. Owens

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Figure 8

Model for epigenetic regulation of SRF binding to CArG box chromatin.

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Model for epigenetic regulation of SRF binding to CArG box chromatin. Gr...
Gray squares represent histone octamers with red DNA strands wrapped around them. The dark lines with Me (methyl groups) and Ac (acetyl groups) protruding from H3 and H4 represent histone tail domains that are subject to H4 and H3 acetylation and H3 Lys4 methylation. In this model, signals such as vascular injury that repress myocardin and/or recruit KLF4-dependent HDAC activity at SMC gene promoters result in loss of SRF binding and transcriptional repression of these genes, to promote the dedifferentiated phenotype. In contrast, in the absence of KLF4, SRF is able to recognize accessible CArG box sequences within “open” chromatin containing H4Ac, synergizing with docking of myocardin to H3K4dMe, to facilitate SRF binding to chromatin and transcriptional activation, which promotes SMC differentiation. The blue protein labeled “??” represents a putative myocardin-accessory factor that may assist myocardin in docking to methylated histones near CArG DNA sequences, to help tether and/or stabilize SRF binding to SMC gene chromatin, which is enriched with H3K4dMe in SMCs.