FHL2 switches MITF from activator to repressor of Erbin expression during cardiac hypertrophy

Abstract

Background Congestive heart failure (CHF) is a significant health care burden in developed countries. However, the molecular events leading from cardiac hypertrophy to CHF are unclear and preventive therapeutic approaches are limited. We have previously described that microphthalmia-associated transcription factor (MITF) plays a key regulator of cardiac hypertrophy, but its cardiac targets are still uncharacterized. Methods and Results Gene array analysis of hearts from MITF-mutated mice indicated ErbB2 interacting protein (Erbin) is a candidate target gene for MITF. We have recently demonstrated that Erbin is decreased in human heart failure and plays as a negative modulator of pathologic cardiac hypertrophy. Here we show that Erbin expression is regulated by MITF. Under basal conditions MITF activates Erbin expression by direct binding to its promoter. However, under β-adrenergic stimulation Erbin expression is decreased only in wild type mice, but not in MITF-mutated mice. Yeast two-hybrid screening, using MITF as bait, identified an interaction with the cardiac-predominant four-and-a-half LIM domains protein 2 (FHL2), which was confirmed by co-immunoprecipitation in both mouse and human hearts. Upon β-adrenergic stimulation, FHL2 and MITF bind Erbin promoter as a complex and repress MITF-directed Erbin expression. Overexpression of FHL2 alone had no effect on Erbin expression, but in the presence of MITF, Erbin expression was decreased. FHL2-MITF association was also increased in biopsies of heart failure patients. Conclusion MITF unexpectedly regulates both the activation and the repression of Erbin expression. This ligand mediated fine tuning of its gene expression and could be an important mechanism in the process of cardiac hypertrophy and heart failure.

A Simple Grammar Defines Activating and Repressing cis-Regulatory Elements in Photoreceptors

“…In some cases, this dual function results from post-translational modifications (Méthot and Basler, 1999; Parker et al, 2011), while in others, binding sites for additional factors encode different activities at different cis-regulatory elements (Alexandre and Vincent, 2003; Martínez-Montañés et al, 2013; Pompeani et al, 2008; Rachmin et al, 2015; Sánchez-Tilló et al, 2015). We have shown here that variation in the number and affinity of binding sites for only a single TF is sufficient to encode activation versus repression.…”

“…Such dual-function TFs occur in organisms from bacteria to mammals (Martínez-Montañés et al, 2013; Pompeani et al, 2008; Liu et al, 2014; Rachmin et al, 2015; Sánchez-Tilló et al, 2015). Because activation and repression occur in the same cell, the response of a target gene to a TF must be encoded in cis-regulatory elements by the specific arrangement, number, affinity, and identity of TF binding sites (Levo and Segal, 2014).…”

MITF interacts with the SWI/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy

“…However, the precise transcriptional mechanisms by which this MITF isoform promotes gene expression in the heart are not well understood. Only, three genes, myosin light-chain 1a (MLC-1a), and erbin have been shown to be directly regulated by MITF in cardiomyocytes [13–15]. Of these three MITF targets, only mir-541 and erbin have a role in cardiac hypertrophy.…”

“…At present, only three genes that are directly regulated by MITF-H in cardiomyocytes have been identified [13–15]. Furthermore, little is known about how MITF-H activity is coordinated with the activities of other transcriptional regulators or with chromatin remodeling enzymes that regulate cardiomyocyte specific gene expression.…”

The master role of microphthalmia-associated transcription factor in melanocyte and melanoma biology

“…47 MITF repressed C/EBPα, a key transcription factor for basophil differentiation, to promote mast cell differentiation 48 and was seen to associate with FHL2 to repress Erbin expression in cardiomyocytes. 49 MITF also repressed ZEB1 transcription in the 501mel human melanoma cell line, 50 as well as inflammation genes through repressing c-Jun expression in mouse and human melanoma cell lines. 51 MITF recruits RBPJK as a cofactor in repressing transcription of microRNAs miR-221 and miR-222 in human melanoma cell lines.…”