Progress on the roles of MEF2C in neuropsychiatric diseases

Myocyte Enhancer Factor 2 C (MEF2C), one of the transcription factors of the MADS-BOX family, is involved in embryonic brain development, neuronal formation and differentiation, as well as in the growth and pruning of axons and dendrites. MEF2C is also involved in the development of various neuropsychiatric disorders, such as autism spectrum disorders (ASD), epilepsy, schizophrenia and Alzheimer’s disease (AD). Here, we review the relationship between MEF2C and neuropsychiatric disorders, and provide further insights into the mechanism of these diseases.

A screen for Twist-interacting proteins identifies Twinstar as a regulator of muscle development during embryogenesis

ABSTRACTMyogenesis in Drosophila relies on the activity of the transcription factor Twist during several key events of mesoderm differentiation. To identify the mechanism(s) by which Twist establishes a unique gene expression profile in specific spatial and temporal locales, we employed a yeast-based double interaction screen to discover new Twist-interacting proteins (TIPs) at the myocyte enhancer factor 2 (mef2) and tinman (tinB) myogenic enhancers. We identified a number of proteins that interacted with Twist at one or both enhancers, and whose interactions with Twist and roles in muscle development were previously unknown. Through genetic interaction studies, we find that Twinstar (Tsr), and its regulators are required for muscle formation. Loss of function and null mutations in tsr and its regulators result in missing and/or misattached muscles. Our data suggest that the yeast double interaction screen is a worthy approach to investigate spatial-temporal mechanisms of transcriptional regulation in muscle and in other tissues.

MEF2 (Myocyte Enhancer Factor 2) Is Essential for Endothelial Homeostasis and the Atheroprotective Gene Expression Program

Objective: Atherosclerosis predominantly forms in regions of oscillatory shear stress while regions of laminar shear stress are protected. This protection is partly through the endothelium in laminar flow regions expressing an anti-inflammatory and antithrombotic gene expression program. Several molecular pathways transmitting these distinct flow patterns to the endothelium have been defined. Our objective is to define the role of the MEF2 (myocyte enhancer factor 2) family of transcription factors in promoting an atheroprotective endothelium. Approach and Results: Here, we show through endothelial-specific deletion of the 3 MEF2 factors in the endothelium, Mef2a, -c, and -d, that MEF2 is a critical regulator of vascular homeostasis. MEF2 deficiency results in systemic inflammation, hemorrhage, thrombocytopenia, leukocytosis, and rapid lethality. Transcriptome analysis reveals that MEF2 is required for normal regulation of 3 pathways implicated in determining the flow responsiveness of the endothelium. Specifically, MEF2 is required for expression of Klf2 and Klf4, 2 partially redundant factors essential for promoting an anti-inflammatory and antithrombotic endothelium. This critical requirement results in phenotypic similarities between endothelial-specific deletions of Mef2a/c/d and Klf2/4. In addition, MEF2 regulates the expression of Notch family genes, Notch1, Dll1, and Jag1, which also promote an atheroprotective endothelium. In contrast to these atheroprotective pathways, MEF2 deficiency upregulates an atherosclerosis promoting pathway through increasing the amount of TAZ (transcriptional coactivator with PDZ-binding motif). Conclusions: Our results implicate MEF2 as a critical upstream regulator of several transcription factors responsible for gene expression programs that affect development of atherosclerosis and promote an anti-inflammatory and antithrombotic endothelium.

Is There Any Association Between the MEF2A Gene Changes and Coronary Artery Disease?

Coronary artery disease (CAD) is a common multifactorial disease with a high rate of morbidity and mortality worldwide. The MEF2A gene transcription factor belongs to the myocyte enhancer factor-2 (MEF2) family and is involved in critical processes such as calcium-dependent signaling pathways and cardiac development. Although the variants of the MEF2A gene were studied in different CAD and myocardial infarction (MI) populations, the reality of this gene association with CAD is still unclear. This study reports the first in silico investigation on MEF2A variants. All reported variants in CAD/MI patients were collected from eleven countries. Their pathogenicity and variant position conservation were surveyed by online prediction tools, including Mutation-Taster, Polyphen-2, PROVEAN, SIFT, CADD, and GERP. In silico analysis did not confirm the pathogenic effect of 21-bp deletion, which was introduced as a monogenic cause of CAD. c.704C>A (p.S235Y), c.812C>G (p.P271R), c.836C>T (p.P279L) and c.848G>A (p.G283D) missenses, c.1315C>T (p.R439X) nonsense, and seven out-of-frame deletions were predicted as disease-causing variants. Although some variants of the MEF2A gene affect protein structure, the MEF2A variation studies in CAD/MI patients and in silico analysis do not approve the association and pathogenicity of MEF2A variants in the familial/sporadic CAD. © 2020 Tehran University

Nuclear GAPDH signaling mediates pathological cardiac hypertrophy

Pathological stressors disrupt cellular and organ homeostasis, causing various diseases. We discovered a novel role for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the pathological growth response of the heart, independent of its functions in glycolysis and cell death. In a cellular model for cardiac hypertrophy, endothelin-1 elicited nuclear translocation of GAPDH and activation of p300 histone acetyl-transferase (HAT), followed by activation of myocyte enhancer factor 2 (MEF2). GAPDH nuclear translocation and p300 HAT activation was also identified in rodent pathological hypertrophied hearts. The hypertrophy was markedly ameliorated by molecular and pharmacological interventions that antagonize the nuclear GAPDH pathway, including a novel antagonist selective to its nuclear function. This pathway may be the key to stress response/homeostatic control, and thus the potential therapeutic target for stress-associated diseases.One-sentence summaryThis study shows a novel function of GAPDH in homeostatic control of the heart, which is disturbed and results in cardiac hypertrophy with pathological stressors.

Common Carp mef2 Genes: Evolution and Expression

The MEF2 (myocyte enhancer factor 2) family belongs to the MADS-box superfamily of eukaryotic transcription factors. The vertebrate genes compose four distinct subfamilies designated MEF2A, -B, -C, and -D. There are multiple mef2 genes in the common carp (Cyprinus carpio). So far, the embryonic expression patterns of these genes and the evolution of fish mef2 genes have been barely investigated. In this study, we completed the coding information of C. carpio mef2ca2 and mef2d1 genes via gene cloning and presented two mosaic mef2 sequences as evidence for recombination. We also analyzed the phylogenetic relationship and conserved synteny of mef2 genes and proposed a new evolutionary scenario. In our version, MEF2B and the other three vertebrate subfamilies were generated in parallel from the single last ancestor via two rounds of whole genome duplication events that occurred at the dawn of vertebrates. Moreover, we examined the expression patterns of C. carpio mef2 genes during embryogenesis, by using whole-mount in situ hybridization, and found the notochord to be a new expression site for these genes except for mef2ca1&2. Our results thus provide new insights into the evolution and expression of mef2 genes.