title: Cooperative activation of cardiac transcription through myocardin bridging of paired MEF2 sites.
abstract: 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, we identify a bona fide cardiac-specificPrkaa2enhancer 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 transcriptionin vivoPaired MEF2 sites are prevalent in cardiac enhancers, suggesting that this might be a common mechanism underlying synergy in the control of cardiac gene expressionin vivo.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Anderson
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Hu
authors.affiliation: Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: T Blair
authors.initials: TB
authors.lastname: Gainous
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Celona
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Tanvi
authors.initials: T
authors.lastname: Sinha
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Diane E
authors.initials: DE
authors.lastname: Dickel
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Analeah B
authors.initials: AB
authors.lastname: Heidt
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.
authors.forename: Shan-Mei
authors.initials: SM
authors.lastname: Xu
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA.|Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.affiliation: Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Pollard
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-3120, USA brian.black@ucsf.edu.|Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.
authors.forename: Brian L
authors.identifier: 0000-0002-6664-8913
authors.initials: BL
authors.lastname: Black
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D004742:Enhancer Elements, Genetic; D064326:MEF2 Transcription Factors / Q000378:metabolism*; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D055503:Protein Multimerization; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D000099251:Myocardin
chemical_list: D055372:AMP-Activated Protein Kinases; D064326:MEF2 Transcription Factors; D009687:Nuclear Proteins; D015534:Trans-Activators; D000099251:Myocardin
keywords: AMPK; MEF2; Mouse; Myocardin; Prkaa2; Transcription