MEF2-dependent recruitment of the HAND1 transcription factor results in synergistic activation of target promoters.
HAND proteins are tissue-restricted members of the basic helix-loop-helix transcription factor family that play critical roles in cell differentiation and organogenesis including placental, cardiovascular, and craniofacial development. Nevertheless, the molecular basis underlying the developmental action of HAND proteins remains undefined. Within the embryo, HAND1 is first detected in the developing heart where it becomes restricted to the atrial and left ventricular compartments, a pattern identical to that of the Nppa gene, which encodes atrial natriuretic factor, the major secretory product of the heart. We hereby report that the cardiac atrial natriuretic factor promoter is directly activated by HAND1, making it the first known HAND1 transcriptional target. The action of HAND1 does not require heterodimerization with class I basic helix-loop-helix factors or DNA binding through E-box elements. Instead, HAND1 is recruited to the promoter via physical interaction with MEF2 proteins. MEF2/HAND1 interaction results in synergistic activation of MEF2-dependent promoters, and MEF2 binding sites are sufficient to mediate this synergy. MEF2 binding to DNA is not enhanced in the presence of HAND1. Instead, cooperativity likely results from corecruitment of co-activators such as CREB-binding protein. The related HAND2 protein can also synergize with MEF2. Thus, HAND proteins act as cell-specific developmental co-activators of the MEF2 family of transcription factors. These findings identify a novel mechanism for HAND action in the heart and provide a general paradigm to understand the mechanism of HAND action in organogenesis.
Morin
Steves
S
Laboratory of Cardiac Growth and Differentiation, Institut de Recherches Cliniques de Montréal (IRCM), Quebec, Canada.
Pozzulo
Gina
G
Robitaille
Lynda
L
Cross
Jay
J
Nemer
Mona
M
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D050882:CREB-Binding Protein; D002460:Cell Line; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D019281:Dimerization; D017353:Gene Deletion; D006367:HeLa Cells; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D064326:MEF2 Transcription Factors; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D018006:Myogenic Regulatory Factors; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry; D015534:Trans-Activators / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D050882:CREB-Binding Protein; D004247:DNA; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C095572:Hand1 protein, mouse; C097341:helix-loop-helix protein, eHAND; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse; C494365:Crebbp protein, rat