MEF2-dependent Recruitment of the HAND1 Transcription Factor Results in Synergistic Activation of Target Promoters

Abstract

HAND proteins are tissue-restricted members of the basic helixloop-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.

Transcriptional Analysis of the Human Cardiac Calsequestrin Gene in Cardiac and Skeletal Myocytes

“…Thus, it is possible that some of these cofactors contribute with SRF to regulate expression of the casq2 gene. The MEF-2 factor has been mentioned to interact with basic helix-loop-helix transcription factors (47,48), even when the E-box site present on the first 140 bp did not show binding capabilities, it is still possible that basic helix-loop-helix factors acting as cofactors of MEF-2 and are involved in regulating the casq2 gene expression.…”

A role for p38α mitogen‐activated protein kinase in embryonic cardiac differentiation

“…Mef2C is a transcription factor expressed early (at E7.5 in mice) during heart development in vertebrates, whose genetic ablation causes morphological and transcriptional abnormalities during early cardiogenesis [4]. A cooperative interaction between Mef2C and other cardiac transcription factors o transcriptional co-activators is essential for synergistic activation of different cardiac promoters, such as ANF by Mef2C and dHAND, or myocardin by cooperation between myocardin and Mef2C, allowing the correct initiation of the cardiac differentiation program [2,3,23,26,30,31]. According to this, in p38a À/À cardiomyocytes, ANF and myocardin expression drastically decrease probably as a consequence of the defect in Mef2C function.…”

A Novel RhoA/ROCK-CPI-17-MEF2C Signaling Pathway Regulates Vascular Smooth Muscle Cell Gene Expression

“…2D). MEF2C has previously been shown to interact with the bHLH transcription factors of the Hand (heart and neural crest derived) family (22). In addition, genetic ablation of MEF2C, dHand (Hand2), and myocardin all result in some degree of neural crest-derived vascular defect (23)(24)(25).…”