Myocyte Enhancer Factor 2C Gene Research Articles

Refining patterns of MEF2C effects in white matter microstructure and psychiatric features.

Several GWAS reported Myocyte Enhancer Factor 2 C (MEF2C) gene associations with white matter microstructure and psychiatric disorders, and MEF2C involvement in pathways related to neuronal development suggests a common biological factor underlying these phenotypes. We aim to refine the MEF2C effects in the brain relying on an integrated analysis of white matter and psychiatric phenotypes in an extensively characterized sample. This study included 870 Brazilian adults (47% from an attention-deficit/hyperactivity disorder outpatient clinic) assessed through standardized psychiatric interviews, 139 of which underwent a magnetic resonance imaging scan. We evaluated variants in the MEF2C region using two approaches: 1) a gene-wide analysis, which uses the sum of polymorphism effects, and 2) SNP analyses, restricted to the independent variants within the gene. The outcomes included psychiatric phenotypes and fractional anisotropy for brain images. Results: The gene-wide analyses pointed to a nominal association between MEF2C and the Temporal Portion of the Superior Longitudinal Fasciculus (SLFTEMP). The SNP analysis identified four independent variants significantly associated with SLFTEMP and one (rs4218438) with Substance Use Disorder. Our findings showing specific associations of MEF2C variants with temporal-frontal circuitry components may help to elucidate how the MEF2C gene underlies a broad range of psychiatric phenotypes since these regions are relevant to executive and cognitive functions.

MEF2C gene variations are associated with ADHD in the Chinese Han population: a case-control study.

Myocyte enhancer factor 2C (MEF2C) is associated with hyperactivity and might be a novel risk gene for susceptibility to attention deficit hyperactivity disorder (ADHD). Therefore, this study aimed to explore the association between MEF2C genetic variants and ADHD in the Chinese Han population. A total of 215 patients with ADHD and 233 controls were recruited for this study. The Swanson, Nolan, and Pelham version IV questionnaire was used to evaluate the clinical features of ADHD. In silico analysis was used to annotate the biological functions of the promising single nucleotide polymorphisms. Our findings indicated that MEF2C rs587490 was significantly associated with ADHD in the multiplicative model (OR = 0.640, p = 0.002). Participants with the rs587490 TT allele exhibited less hyperactivity/impulsivity than those with the rs587490 CC allele. Furthermore, the expression quantitative trait loci analysis suggested that rs587490 could regulate the gene expression of MEF2C in the hippocampus, putamen, thalamus, and frontal white matter. Our study concluded that the MEF2C rs587490 T allele is significantly associated with a reduced risk of ADHD in the Chinese Han population, which provides new insight into the genetic etiology of ADHD.

Effect of Three Therapeutic Methods of Exercise, Ozone, and Stem Cells on the MEF2C Expression and Myostatin Levels in Femoral Muscle Tissue of the Osteoarthritis Rats

Aims: Myostatin and Myocyte Enhancer Factor 2C (MEF2C) are involved in muscle changes associated with bone problems. The aim of the present study was to determine the effect of three therapeutic methods of exercise, ozone, and stem cells on MEF-2C gene expression and myostatin levels of femoral muscle tissue in osteoarthritis rats. Methods & Materials: This experimental study was done on 63 male rats (mean age of 8-12 weeks and weight of 250-300 g). They were randomly divided into nine groups: the healthy control and osteoarthritis group and seven intervention groups of osteoarthritis rats, including , saline, exercise, ozone therapy, MSCs, MSCs+ozone therapy, exercise+ozone therapy, and exercise+MSCs. Osteoarthritis was induced in rats by surgery. The training program consisted of 30 min of running on a non-slip treadmill at a speed of 16 m/min. Rats in the MSCs group received 1×106 cells/kg. The ozone was injected into the articular line of the knee tibiofemoral at a concentration of 20 μg/mL. Tissue levels of myostatin were measured by enzyme-linked immunosorbent assay kits and MEF2C gene expression was measured by real-time polymerase chain reaction method. Findings: Cell+exercise, exercise+ozone, and cell+ozone groups showed a significant increase in MEF2C gene expression and a significant decrease in myostatin levels compared with the cell, exercise, and ozone groups (P<0.05). In the exercise+cell group, these changes were greater. Conclusion: The results showed that the combination of exercise and MSCs with an increase in MEF2C gene expression and a decrease in myostatin levels, can possibly have beneficial effects on the stimulatory and inhibitory factors of interactions between muscle and bone in the osteoarthritis rats, and ultimately reduce the risks of muscle weakness due to osteoarthritis complications.

Identification of the Regulatory Elements and Target Genes of Megakaryopoietic Transcription Factor MEF2C.

Megakaryopoiesis produces specialized haematopoietic stem cells in the bone marrow that give rise to megakaryocytes which ultimately produce platelets. Defects in megakaryopoiesis can result in altered platelet counts and physiology, leading to dysfunctional haemostasis and thrombosis. Additionally, dysregulated megakaryopoiesis is also associated with myeloid pathologies. Transcription factors play critical roles in cell differentiation by regulating the temporal and spatial patterns of gene expression which ultimately decide cell fate. Several transcription factors have been described as regulating megakaryopoiesis including myocyte enhancer factor 2C (MEF2C); however, the genes regulated by MEF2C that influence megakaryopoiesis have not been reported. Using chromatin immunoprecipitation-sequencing and Gene Ontology data we identified five candidate genes that are bound by MEF2C and regulate megakaryopoiesis: MOV10, AGO3, HDAC1, RBBP5 and WASF2. To study expression of these genes, we silenced MEF2C gene expression in the Meg01 megakaryocytic cell line and in induced pluripotent stem cells by CRISPR/Cas9 editing. We also knocked down MEF2C expression in cord blood-derived haematopoietic stem cells by siRNA. We found that absent or reduced MEF2C expression resulted in defects in megakaryocytic differentiation and reduced levels of the candidate target genes. Luciferase assays confirmed that genomic sequences within the target genes are regulated by MEF2C levels. Finally, we demonstrate that small deletions linked to a platelet count-associated single nucleotide polymorphism alter transcriptional activity, suggesting a mechanism by which genetic variation in MEF2C alters platelet production. These data help elucidate the mechanism behind MEF2C regulation of megakaryopoiesis and genetic variation driving platelet production.

The novel mutations in the MEF2C gene associate with growth of Nanjiang Yellow goats

The myocyte enhancer factor 2 (MEF2) factors act as lynchpins in cell differentiation and organogenesis through transcriptional circuits and thus potentiate development of vertebrate. Nevertheless, the association between mutations in Myocyte enhancer factor 2 (MEF2s) especially MEF2C (Myocyte enhancer factor 2C) and livestock growth remains largely unknown. Here, in Nanjiang Yellow goat population (female, n = 219), we identified 10 single nucleotide variations (SNVs) in MEF2C using direct Sanger sequencing PCR product from DNA and cDNA. Among which eight were located in exons while two (g.143180 T>G and g.143666 C>T) were in introns, and the only one mutation embedded in coding region (g. 143515 C>T) led to a Pro 148 Ser exchange. In this goat population, all these ten SNVs presented lower to moderate polymorphism (0.28 < PIC < 0.48), and complied with Hardy-Weinberg Equilibrium proportions (P > 0.05). Notably, four SNVs including g.76303 A>G, g.143180 T>G, g.176090 A>G, and g.176845 T>C significantly associated with goat growth (p < 0.07), and the striking body mass connecting to g.143180 T>G variation even exceeded those H3H4 animals by over ~20% from birth to 12-mon old (p < 0.05). Furthermore, g.143180 T>G variation exhibited no connection with exon α splicing of MEF2C, but in silicon analysis revealed that T to G mutation potentially increased DNA accessibility of g.143180 T>G per se and the following 14-bp region by 2 to 22 fold, which directly relates the binding of dlx5 (Distal-Less Homeobox 5). These results confirm the close relationship between MEF2C and animal development, and also provide an important option guiding study in elucidating the substantial mechanisms that MEF2C exerts in promoting mammal growth.

MEF2C rs190982 polymorphism with late-onset Alzheimer's disease in Han Chinese: A replication study and meta-analyses.

The myocyte enhancer factor (MEF2) family of transcription factors plays a vital role in memory and learning due to its functions in regulating synapse number and reducing dendritic spines. Myocyte enhancer factor 2 C (MEF2C) is regarded as modulator of amyloid-protein precursor (APP) proteolytic processing, in which amyloid-β (Aβ) is produced. A common single nucleotide polymorphism (SNP, rs190982) in MEF2C gene was identified to be related to late-onset Alzheimer's disease (LOAD) in Caucasians in a large meta-analysis of genome-wide association studies (GWAS). Here, we recruited unrelated 984 LOAD patients and 1348 healthy controls matched for gender and age to ascertain whether the rs190982 polymorphism is related to LOAD in Han Chinese. No difference in the genotype and allele distributions of the MEF2C rs190982 polymorphism was found between LOAD cases and healthy controls (genotype: P = 0.861; allele: P = 0.862), even after stratification for APOE ε4 allele as well as statistical adjustment for age, gender and APOE ε4 status. Furthermore, the meta-analysis in 4089 Chinese individuals did not detect the association of rs190982 within MEF2C with the risk for LOAD (OR = 1.03, 95%CI = 0.90-1.18). Overall, the current evidence did not support the relation between rs190982 polymorphism within MEF2C and the LOAD risk in Northern Han Chinese.

Variants and haplotypes within MEF2C gene influence stature of chinese native cattle including body dimensions and weight

Myocyte enhancer factor 2C (MEF2C) gene was annotated for its potential phenotypic effects on bovine stature including body dimensions and body weight. The aim of this study was the analysis of MEF2C as a candidate for bovine stature. Four SNPs including two novel SNPs were identified and the polymorphisms were genotyped by (forced) PCR-RFLP. Using a population of 805 cows from two Chinese native breeds, we report confirmation of this effect, demonstrating strong association of different components of bovine stature with MEF2C genotypes. Six combined haplotypes were constructed as well and diplotype H1H6/H3H5 (CTGGTCAA) affected bovine stature negatively, including body weight, hucklebone widt, and withers height (P<0.05). Our results suggest that the four variants within bovine MEF2C can be used as candidate SNP markers for marker-assisted selection in beef cattle breeding programmes.

RBM4-MEF2C network constitutes a feed-forward circuit that facilitates the differentiation of brown adipocytes

Myocyte enhancer factor 2c (MEF2C) is the MADS-box type transcription factor involved in the differentiation of cardiac and skeletal muscle and synaptic formation. Alternatively spliced transcripts of the MEF2C gene were proven to encode isoforms which exert distinct functions in transcriptional regulation. During the differentiation of brown adipocytes, upregulated RBM4 enhanced skipping of the MEF2Cγ region which functions as a transcriptional repressor. The presence of an overexpressed MEF2Cγ- isoform in turn induced transcriptional activity of the RBM4 promoter, constituting a positive feedback circuit in differentiating brown adipocytes. The RBM4-MEF2Cγ- network induced the expression of "myogenic" miR-1 to a greater extent than did PRDM17, BMP7 C/EBPβ, or UCP1 transcripts in C3H10T1/2 cells. Overexpression of miR-1 independently exerted the same activity as RBM4 and the MEF2Cγ- isoform of upregulating brown adipocyte-specific factors in C3H10T1/2 cells, which suggests a potential effect of miR-1 on brown adipocytes. These results indicated that the RBM4-MEF2C-miR-1 network constitutes a novel mechanism which programs the gene expression profile toward the development of brown adipocytes.

De novo microdeletion of 5q14.3 excluding MEF2C in a patient with infantile spasms, microcephaly, and agenesis of the corpus callosum

The 5q14.3 microdeletion syndrome has recently been recognized as a clinical entity manifesting as severe intellectual disability, epilepsy, and brain malformations. Analysis of the shortest region of overlap among patients with this syndrome and subsequent identification of nucleotide alterations in the coding region of myocyte enhancer factor 2C gene (MEF2C) have suggested MEF2C as the gene responsible for the 5q14.3 microdeletion syndrome. We identified a de novo 3.4-Mb deletion of 5q14.3 in a patient with infantile spasms, microcephaly, and brain malformation. The deleted region in the present patient was positional toward the centromere, and MEF2C was not included in the deleted region. However the neurological and dysmorphic features of the present patient resembled those of patients with the 5q14.3 microdeletion syndrome. We consider that a positional effect is the likely explanation for this evidence. To study the precise mechanism of this positional effect, further information is required on patients showing atypical deletions neighboring MEF2C.

Nucleotide sequence and variations of the bovine myocyte enhancer factor 2C (MEF2C) gene promoter in Bos Taurus cattle

Myocyte Enhancer Factor 2 (MEF2) proteins are a small family of transcription factors that play pivotal role in morphogenesis and myogenesis of skeletal, cardiac, and smooth muscle cells. In vertebrates, there are four MEF2 genes, referred to as MEF2A, -B, -C, and -D, that are located on different chromosomes. After birth MEF2A, MEF2B, MEF2D transcriptions are expressed ubiquitously, whereas MEF2C transcripts are restricted to skeletal muscle, brain, and spleen. In this study, on the basis of the sequences of the bovine chromosome 7 genomic contig, available in the GenBank database, sets of PCR primers were designed and to amplify the bovine MEF2C gene promoter region, exon 1 (5′UTR) and part sequence of the intron 1. Seven overlapping fragments of the bovine MEF2C gene were amplified and then sequenced. Altogether, these fragments were composed in the 3,120-bp sequence which was deposited in the GenBank database under accession no. GU211007. The sequence fragment included the putative site of the promoter region and transcription start of the exon 1. The sequence analysis of these fragments in individual animals representing different Bos taurus breeds revealed four variations in promoter region: g.-1606C>T, g.-1336_-1335DelG, g.-818C>T, g.-613_-612DelA and four SNPs within intron 1: g.2711A>G, g. 2913A>G, g.2962G>T and g.3014A>G. No polymorphism was found within sequence of the exon 1 (5′UTR). These polymorphisms were identified for first time using these sequences and were confirmed by RFLP or MSSCP methods.

Maturation of the myogenic program is induced by postmitotic expression of insulin-like growth factor I.

The molecular mechanisms underlying myogenic induction by insulin-like growth factor I (IGF-I) are distinct from its proliferative effects on myoblasts. To determine the postmitotic role of IGF-I on muscle cell differentiation, we derived L6E9 muscle cell lines carrying a stably transfected rat IGF-I gene under the control of a myosin light chain (MLC) promoter-enhancer cassette. Expression of MLC-IGF-I exclusively in differentiated L6E9 myotubes, which express the embryonic form of myosin heavy chain (MyHC) and no endogenous IGF-I, resulted in pronounced myotube hypertrophy, accompanied by activation of the neonatal MyHC isoform. The hypertrophic myotubes dramatically increased expression of myogenin, muscle creatine kinase, beta-enolase, and IGF binding protein 5 and activated the myocyte enhancer factor 2C gene which is normally silent in this cell line. MLC-IGF-I induction in differentiated L6E9 cells also increased the expression of a transiently transfected LacZ reporter driven by the myogenin promoter, demonstrating activation of the differentiation program at the transcriptional level. Nuclear reorganization, accumulation of skeletal actin protein, and an increased expression of beta1D integrin were also observed. Inhibition of the phosphatidyl inositol (PI) 3-kinase intermediate in IGF-I-mediated signal transduction confirmed that the PI 3-kinase pathway is required only at early stages for IGF-I-mediated hypertrophy and neonatal MyHC induction in these cells. Expression of IGF-I in postmitotic muscle may therefore play an important role in the maturation of the myogenic program.