Cooperative activation of cardiac transcription through myocardin bridging of paired MEF2 sites
- Univ. of California, San Francisco, CA (United States). Cardiovascular Research Inst.
- Univ. of California, San Francisco, CA (United States). Gladstone Inst.
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Genomics Division
- Univ. of California, San Francisco, CA (United States). Cardiovascular Research Inst.; Univ. of California, San Francisco, CA (United States). Gladstone Inst.
- Univ. of California, San Francisco, CA (United States). Cardiovascular Research Inst.; Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics
Enhancers frequently contain multiple binding sites for the same transcription factor. These homotypic binding sites often exhibit synergy, whereby the transcriptional output from two or more binding sites is greater than the sum of the contributions of the individual binding sites alone. Although this phenomenon is frequently observed, the mechanistic basis for homotypic binding site synergy is poorly understood. Here in this paper, we identify a bona fide cardiac-specific Prkaa2 enhancer that is synergistically activated by homotypic MEF2 binding sites. We show that two MEF2 sites in the enhancer function cooperatively due to bridging of the MEF2C-bound sites by the SAP domain-containing co-activator protein myocardin, and we show that paired sites buffer the enhancer from integration site-dependent effects on transcription in vivo. Paired MEF2 sites are prevalent in cardiac enhancers, suggesting that this might be a common mechanism underlying synergy in the control of cardiac gene expression in vivo.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- National Institutes of Health (NIH); USDOE
- DOE Contract Number:
- AC02-05CH11231; T32 HL007544; HL089707; HL064658; R24HL123879; UM1HL098166; U01DE024427; R01HG003988; U54HG006997
- OSTI ID:
- 1393211
- Journal Information:
- Development (Cambridge), Vol. 144, Issue 7; ISSN 0950-1991
- Publisher:
- Company of Biologists
- Country of Publication:
- United States
- Language:
- English
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