MEF2C
Myocyte-specific enhancer factor 2C (Myocyte enhancer factor 2C)
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While autologous stem cell-based therapies are currently being tested on elderly patients, there are limited data on the function of aged stem cells and in particular c-kit cardiac progenitor cells (CPCs). We isolated c-kit cells from young (3 months) and aged (24 months) C57BL/6 mice to compare their biological properties. Aged CPCs have increased senescence, decreased stemness and reduced capacity to proliferate or to differentiate following dexamethasone (Dex) treatment in vitro, as evidenced by lack of cardiac lineage gene upregulation. Aged CPCs fail to activate mitochondrial biogenesis and increase proteins involved in mitochondrial oxidative phosphorylation in response to Dex. Aged CPCs fail to upregulate paracrine factors that are potentially important for proliferation, survival and angiogenesis in response to Dex. The results highlight marked differences between young and aged CPCs, which may impact future design of autologous stem cell-based therapies. Therapeutic use of c-kit cardiac progenitor cells (CPCs) is being evaluated for regenerative therapy in older patients with ischaemic heart failure. Our understanding of the biology of these CPCs has, however, largely come from studies of young cells and animal models. In the present study we examined characteristics of CPCs isolated from young (3 months) and aged (24 months) mice that could underlie the diverse outcomes reported for CPC-based therapeutics. We observed morphological differences and altered senescence indicated by increased senescence-associated markers β-galactosidase and p16 mRNA in aged CPCs. The aged CPCs also proliferated more slowly than their young counterparts and expressed lower levels of the stemness marker LIN28. We subsequently treated the cells with dexamethasone (Dex), routinely used to induce commitment in CPCs, for 7 days and analysed expression of cardiac lineage marker genes. While MEF2C, GATA4, GATA6 and PECAM mRNAs were significantly upregulated in response to Dex treatment in young CPCs, their expression was not increased in aged CPCs. Interestingly, Dex treatment of aged CPCs also failed to increase mitochondrial biogenesis and expression of the mitochondrial proteins Complex III and IV, consistent with a defect in mitochondria complex assembly in the aged CPCs. Dex-treated aged CPCs also had impaired ability to upregulate expression of paracrine factor genes and the conditioned media from these cells had reduced ability to induce angiogenesis in vitro. These findings could impact the design of future CPC-based therapeutic approaches for the treatment of older patients suffering from cardiac injury.
MeSH Terms
- Adult Stem Cells
- Aging
- Animals
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Cellular Senescence
- Dexamethasone
- Electron Transport Chain Complex Proteins
- GATA Transcription Factors
- MEF2 Transcription Factors
- Male
- Mice
- Mice, Inbred C57BL
- Myocytes, Cardiac
- Organelle Biogenesis
- Platelet Endothelial Cell Adhesion Molecule-1
- Proto-Oncogene Proteins c-kit
- RNA, Messenger
- RNA-Binding Proteins
Keywords
- aging
- c-kit
- cardiac progenitor cells
- stem cell
Genome-wide association studies and meta-analyses implicated that increased risk of developing Alzheimer's diseases (AD) has been associated with the ABCA7, APOE, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB1, HLA-DRB4, INPP5D, MEF2C, MS4A4A, MS4A4E, MS4A6E, NME8, PICALM, PLD3, PTK2B, RIN3, SLC24A4, SORL1, and ZCWPW1 genes. In this study, we assessed whether single nucleotide polymorphisms (SNPs) within these 27 AD-associatedgenes are linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. We also analyzed the interactions between lifestyle and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examination (MMSE) scores were performed for all subjects to evaluate cognitive functions. Out of the 588 SNPs tested in this study, only the association between CASS4-rs911159 and cognitive aging persisted significantly (P = 2.2 x 10-5) after Bonferroni correction. Our data also showed a nominal association of cognitive aging with the SNPs in six more key AD-associated genes, including EPHA1-rs10952552, FERMT2-rs4901317, MEF2C-rs9293506, PLD3-rs11672825, RIN3-rs1885747, and SLC24A4-rs67063100 (P = 0.0018~0.0097). Additionally, we found the interactions among CASS4-rs911159, EPHA-rs10952552, FERMT2-rs4901317, MEF2C-rs9293506, or SLC24A4-rs67063100 on cognitive aging (P = 0.004~0.035). Moreover, our analysis suggested the interactions of SLC24A4-rs67063100 or MEF2C-rs9293506 with lifestyle such as alcohol consumption, smoking status, physical activity, or social support on cognitive aging (P = 0.008~0.041). Our study indicates that the AD-associated genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-lifestyle interactions.
MeSH Terms
- Age Factors
- Aged
- Alleles
- Alzheimer Disease
- Cognitive Aging
- Epistasis, Genetic
- Female
- Gene-Environment Interaction
- Genetic Association Studies
- Genetic Predisposition to Disease
- Humans
- Life Style
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Risk Factors
- Taiwan
Keywords
- Alzheimer’s diseases
- Gerotarget
- Mini-Mental State Examination
- cognitive aging
- gene-gene and gene-lifestyle interactions
- single nucleotide polymorphisms
Bone mineral density (BMD) is a heritable phenotype that predicts fracture risk. We performed fine-mapping by targeted sequencing at WLS, MEF2C, ARHGAP1/F2 and JAG1 loci prioritized by eQTL and bioinformatic approaches among 56 BMD loci from our previous GWAS meta-analysis. Targeted sequencing was conducted in 1,291 Caucasians from the Framingham Heart Study ( n = 925) and Cardiovascular Health Study ( n = 366), including 206 women and men with extreme low femoral neck (FN) BMD. A total of 4,964 sequence variants (SNVs) were observed and 80% were rare with MAF <1%. The associations between previously identified SNPs in these loci and BMD, while nominally significant in sequenced participants, were no longer significant after multiple testing corrections. Conditional analyses did not find protein-coding variants that may be responsible for GWAS signals. On the other hand, in the sequenced subjects, we identified novel associations in WLS , ARHGAP1 , and 5' of MEF2C ( P- values < 8x10 - 5 ; false discovery rate (FDR) q-values < 0.01) that were much more strongly associated with BMD compared to the GWAS SNPs. These associated SNVs are less-common; independent from previous GWAS signals in the same loci; and located in gene regulatory elements. Our findings suggest that protein-coding variants in selected GWAS loci did not contribute to GWAS signals. By performing targeted sequencing in GWAS loci, we identified less-common and rare non-coding SNVs associated with BMD independently from GWAS common SNPs, suggesting both common and less-common variants may associate with disease risks and phenotypes in the same loci.
MeSH Terms
- Aging
- Bone Density
- Cardiovascular Diseases
- Cohort Studies
- Epidemiologic Studies
- Female
- Femur Neck
- GTPase-Activating Proteins
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- MEF2 Transcription Factors
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
The transcription factor MEF2C (Myocyte Enhancer Factor 2C) plays an established role in the early steps of myogenic differentiation. However, the involvement of MEF2C in adult myogenesis and in muscle regeneration has not yet been systematically investigated. Alternative splicing of mammalian MEF2C transcripts gives rise to two mutually exclusive protein variants: MEF2Cα2 which exerts a positive control of myogenic differentiation, and MEF2Cα1, in which the α1 domain acts as trans-repressor of the MEF2C pro-differentiation activity itself. However, MEF2Cα1 variants are persistently expressed in differentiating cultured myocytes, suggesting a role in adult myogenesis. We found that overexpression of both MEF2Cα1/α2 proteins in a mouse model of muscle injury promotes muscle regeneration and hypertrophy, with each isoform promoting different stages of myogenesis. Besides the ability of MEF2Cα2 to increase differentiation, we found that overexpressed MEF2Cα1 enhances both proliferation and differentiation of primary myoblasts, and activates the AKT/mTOR/S6K anabolic signaling pathway in newly formed myofibers. The multiple activities of MEF2Cα1 are modulated by phosphorylation of Ser98 and Ser110, two amino acid residues located in the α1 domain of MEF2Cα1. These specific phosphorylations allow the interaction of MEF2Cα1 with the peptidyl-prolyl isomerase PIN1, a regulator of MEF2C functions. Overall, in this study we established a novel regulatory mechanism in which the expression and the phosphorylation of MEF2Cα1 are critically required to sustain the adult myogenesis. The described molecular mechanism will represent a new potential target for the development of therapeutical strategies to treat muscle-wasting diseases. Stem Cells 2017;35:725-738.
MeSH Terms
- Aging
- Alternative Splicing
- Amino Acid Sequence
- Animals
- Cell Differentiation
- Cell Proliferation
- Cells, Cultured
- Hypertrophy
- MEF2 Transcription Factors
- Mice
- Mice, Inbred C57BL
- Muscle, Skeletal
- Myoblasts
- NIH 3T3 Cells
- NIMA-Interacting Peptidylprolyl Isomerase
- Phosphorylation
- Protein Binding
- Protein Domains
- Regeneration
- Satellite Cells, Skeletal Muscle
- Serine
Keywords
- Alternative splicing
- Differentiation
- Hypertrophy
- MEF2 transcription factors
- Myogenesis
- Peptidyl-prolyl isomerase
- Phosphorylation
- Pin1
- Tissue regeneration
Single nucleotide polymorphisms (SNPs) in and near ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, complement receptor 1 (CR1), EPHA1, EXOC3L2, FERMT2, HLA cluster (DRB5-DQA), INPP5D, MEF2C, MS4A cluster (MS4A3-MS4A6E), NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1 have been associated with Alzheimer's disease (AD) in large meta-analyses. We aimed to determine whether established AD-associated genes are associated with longitudinal cognitive decline by examining aggregate variation across these gene regions. In two single-sex cohorts of older, community-dwelling adults, we examined the association between SNPs in previously implicated gene regions and cognitive decline (age-adjusted person-specific cognitive slopes) using a Sequence Kernel Association Test (SKAT). In regions which showed aggregate significance, we examined the univariate association between individual SNPs in the region and cognitive decline. Only two of the original AD-associated SNPs were significantly associated with cognitive decline in our cohorts. We identified significant aggregate-level associations between cognitive decline and the gene regions BIN1, CD33, CELF1, CR1, HLA cluster, and MEF2C in the all-female cohort and significant associations with ABCA7, HLA cluster, MS4A6E, PICALM, PTK2B, SLC24A4, and SORL1 in the all-male cohort. We also identified a block of eight correlated SNPs in CD33 and several blocks of correlated SNPs in CELF1 that were significantly associated with cognitive decline in univariate analysis in the all-female cohort.
MeSH Terms
- Aged
- Aging
- Alzheimer Disease
- Cognition Disorders
- DNA
- Female
- Genetic Association Studies
- Genetic Predisposition to Disease
- Humans
- Male
- Polymorphism, Single Nucleotide
Keywords
- Candidate AD genes
- Cognitive decline
- SNP associations
The aim of this study was to analyze the level of expression of the Mef2C gene in the developing bovine longissimus dorsi (LD) muscle (at 6, 9 and 12months of age) and to evaluate differences in expression among Polish Holstein-Friesian (HO) and Limousine (LM) bulls. Moreover, the expression patterns of Mef2C in different tissues were determined. The results showed that Mef2C mRNA was expressed at a high level in adult skeletal and cardiac muscles. Moreover, Mef2C expression was markedly lower in the semitendinosus (ST) than in the gluteus medius (GM) and LD muscles. A relatively higher Mef2C mRNA and MEF2C protein level was estimated in the muscles of HO bulls at the age of 12months in comparison with its lower expression in LM bulls. Furthermore, we found that the Mef2C promoter variant (GU211004:g.-1606C>T) does not affect the level of mRNA in the LD and ST muscles of 12-month-old HO bulls.
MeSH Terms
- Age Factors
- Aging
- Animals
- Blotting, Western
- Cattle
- MEF2 Transcription Factors
- Male
- Muscle, Skeletal
- Myocardium
- Polymorphism, Genetic
- RNA, Messenger
- Real-Time Polymerase Chain Reaction
- Transcriptome
Keywords
- Cattle
- Gene expression
- Mef2C
- Myogenesis
- Skeletal muscle