title: Regulation of cardiac microRNAs by serum response factor.
abstract: Serum response factor (SRF) regulates certain microRNAs that play a role in cardiac and skeletal muscle development. However, the role of SRF in the regulation of microRNA expression and microRNA biogenesis in cardiac hypertrophy has not been well established. In this report, we employed two distinct transgenic mouse models to study the impact of SRF on cardiac microRNA expression and microRNA biogenesis. Cardiac-specific overexpression of SRF (SRF-Tg) led to altered expression of a number of microRNAs. Interestingly, downregulation of miR-1, miR-133a and upregulation of miR-21 occurred by 7 days of age in these mice, long before the onset of cardiac hypertrophy, suggesting that SRF overexpression impacted the expression of microRNAs which contribute to cardiac hypertrophy. Reducing cardiac SRF level using the antisense-SRF transgenic approach (Anti-SRF-Tg) resulted in the expression of miR-1, miR-133a and miR-21 in the opposite direction. Furthermore, we observed that SRF regulates microRNA biogenesis, specifically the transcription of pri-microRNA, thereby affecting the mature microRNA level. The mir-21 promoter sequence is conserved among mouse, rat and human; one SRF binding site was found to be in the mir-21 proximal promoter region of all three species. The mir-21 gene is regulated by SRF and its cofactors, including myocardin and p49/Strap. Our study demonstrates that the downregulation of miR-1, miR-133a, and upregulation of miR-21 can be reversed by one single upstream regulator, SRF. These results may help to develop novel therapeutic interventions targeting microRNA biogenesis.
authors.affiliation: Donald W., Reynolds Department of Geriatrics, The University of Arkansas for Medical Sciences and Geriatric Research, Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Zhang
authors.forename: Gohar
authors.initials: G
authors.lastname: Azhar
authors.forename: Scott A
authors.initials: SA
authors.lastname: Helms
authors.forename: Jeanne Y
authors.initials: JY
authors.lastname: Wei
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D051381:Rats; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation; D000099251:Myocardin
chemical_list: D035683:MicroRNAs; D009687:Nuclear Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000099251:Myocardin; C531950:MIRN21 microRNA, mouse; C517731:Mirn1 microRNA, mouse; C517732:Mirn133 microRNA, mouse; C496544:p49-STRAP protein, mouse