Cooperative Interaction between the Basic Helix-loop-helix Transcription Factor dHAND and Myocyte Enhancer Factor 2C Regulates Myocardial Gene Expression

Cardiac-restricted transcription factors dHAND and myocyte enhancer factor 2C are expressed in the developing heart and activate several cardiac promoters. However, their regulatory mechanisms are still to be understood. To elucidate their exact regulatory functions, we have developed an RNA interfe...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-12, Vol.279 (52), p.54258-54263
Main Authors: Zang, Ming-Xi, Li, Yong, Wang, Hao, Wang, Jun-Bo, Jia, Hong-Ti
Format: Article
Language:English
Subjects:
Animals
Atrial Natriuretic Factor - genetics
Basic Helix-Loop-Helix Transcription Factors
Binding Sites
Cell Line
Chromatin - chemistry
DNA - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - physiology
Drug Interactions
Drug Synergism
Embryo, Mammalian
Gene Expression
Gene Expression Regulation
Immunosorbent Techniques
MEF2 Transcription Factors
Myocardium - chemistry
Myocardium - metabolism
Myogenic Regulatory Factors - genetics
Myogenic Regulatory Factors - physiology
Myosin Heavy Chains - genetics
Phenylephrine - pharmacology
Promoter Regions, Genetic - genetics
Rats
RNA, Small Interfering - genetics
Transcription Factors - genetics
Transcription Factors - physiology
Transcription, Genetic - drug effects
Transfection
Ventricular Myosins - genetics
Zebrafish Proteins
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Summary:Cardiac-restricted transcription factors dHAND and myocyte enhancer factor 2C are expressed in the developing heart and activate several cardiac promoters. However, their regulatory mechanisms are still to be understood. To elucidate their exact regulatory functions, we have developed an RNA interference strategy to specifically inhibit dHAND and myocyte enhancer factor 2C protein production in H9c2 cells, which are derived from rat embryonic heart. Expression of endogenous cardiac genes atrial natriuretic peptide and α-myosin heavy chain was down-regulated in H9c2 cells lacking both dHAND and myocyte enhancer factor 2C, indicating that these factors are required for the maintenance of the cardiac genetic program. Consistent with these, expression of atrial natriuretic peptide and α-myosin heavy chain was up-regulated in H9c2 cells, which overexpressed dHAND and myocyte enhancer factor 2C. In addition, dHAND and myocyte enhancer factor 2C interact to synergistically activate atrial natriuretic peptide and α-myosin heavy chain transcription. Furthermore, chromatin immunoprecipitation analysis in H9c2 cells treated with phenylephrine showed that dHAND and myocyte enhancer factor 2C protein complex bind to the A/T sequence on atrial natriuretic peptide promoter. Taken together, these results not only suggest that the complex cis-trans interaction of dHAND, myocyte enhancer factor 2C, and the target gene may fine-tune gene expression in cardiac myocytes but also provide a molecular paradigm to elucidate the mechanisms of action of dHAND and myocyte enhancer factor 2C in the developing heart.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M408502200