The Histone Demethylase, Jmjd1a, Interacts With the Myocardin Factors to Regulate SMC Differentiation Marker Gene Expression

Abstract

Abstract-We and others have previously shown that the myocardin transcription factors play critical roles in the regulation of smooth muscle cell (SMC) differentiation marker gene expression. In a yeast 2-hybrid screen for proteins that interact with myocardin-related transcription factor-A (MRTF-A), we identified the histone 3 lysine 9 (H3K9)-specific demethylase, Jmjd1a. GST pull-down assays demonstrated that Jmjd1a bound all 3 myocardin family members, and further mapping studies showed that the jumonjiC domain of Jmjd1a was sufficient to mediate this interaction. Overexpression of Jmjd1a in multipotential 10T1/2 cells decreased global levels of di-methyl H3K9, stimulated the SM ␣-actin and SM22 promoters, and synergistically enhanced MRTF-A-and myocardin-dependent transactivation. Using chromatin immunoprecipitation assays, we also demonstrated that TGF-␤-mediated upregulation of SMC differentiation marker gene expression in 10T1/2 cells was associated with decreased H3K9 dimethylation at the CArG-containing regions of the SMC differentiation marker gene promoters. Importantly, knockdown of Jmjd1a in 10T1/2 cells and primary rat aortic SMCs by retroviral delivery of siRNA attenuated TGF-␤-induced upregulation of endogenous SM myosin heavy chain expression. These effects were concomitant with increased H3K9 dimethylation at the SMC differentiation marker gene promoters and with inhibition of MRTF-A-dependent transactivation of the SMC-specific transcription. These results suggest, for the first time, that SMC differentiation marker gene expression is regulated by H3K9 methylation and that the effects of the myocardin factors on SMC-specific transcription may involve the recruitment of Jmjd1a to the SMC-specific promoters. (Circ Res. 2007;101:e115-e123.)Key Words: SRF Ⅲ myocardin factors Ⅲ histone methylation Ⅲ jumonjiC domain Ⅲ smooth muscle

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…Consistent with these data, KDM3B expression induces leukemic transformation by inhibiting leukemia cell differentiation and is upregulated in blood cells obtained from certain types of leukemia patients [82].…”

“…The myocardin transcription factor interacts with KDM3A and recruits it to SMC-specific gene promoters. KDM3A subsequently demethylates H3K9me3 from these genomic regions and regulates their TGFß-mediated activation [82].…”

MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex

“…Our previous study has found that MRTF-A can drive the transcription of adhesion molecules in vascular endothelial cells by directly interacting with the p65 subunit of NF-kB (Fang et al, 2011). The ability of MRTF-A to steer transcriptional events is derived in part from its extensive crosstalk with the epigenetic machinery, including histone modifying enzymes and chromatin remodeling proteins (Hanna et al, 2009;Lockman et al, 2007;Yang et al, 2013;Zhang et al, 2007;Zhou et al, 2009). Building on these findings, we hypothesized that MRTF-A could fine-tune LPS-induced NFkB-dependent pro-inflammatory transcription in macrophages.…”

Histone Methyltransferase SETD3 Regulates Muscle Differentiation

“…Histone demethylase LSD1 plays a key role in muscle differentiation by controlling epigenetic marks in the myogenin and myosin heavy chain gene promoters (21). Jmjd1a demethylates H3K9 in the myosin heavy chain gene promoter and enhances muscle differentiation by interacting with myocardin factors (22).…”