Chromatin environment and cellular context specify compensatory activity of paralogous MEF2 transcription factors
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ABSTRACT:
PROVIDER: PRJNA574197 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10187204.fastq.gz | Fastqsanger.gz | |||
| SRR10187205.fastq.gz | Fastqsanger.gz | |||
| SRR10187206.fastq.gz | Fastqsanger.gz | |||
| SRR10187207.fastq.gz | Fastqsanger.gz | |||
| SRR10187208.fastq.gz | Fastqsanger.gz |
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Project description:Compensation among paralogous transcription factors (TFs) confers genetic robustness of cellular processes. Despite the prevalence of this phenomenon, an in vivo genome-scale understanding of how TFs dynamically respond to paralog depletion is still needed. We explore this question in the mammalian brain by studying the highly conserved MEF2 family of TFs, which confer phenotypic robustness in multiple brain regions. Employing single and double conditional knockout of MEF2A and MEF2D in granule neurons of the mouse cerebellum, we find MEF2A and MEF2D play functionally redundant roles in cerebellar-dependent motor learning. To explore the molecular basis underlying this phenomenon, we systematically characterize in vivo genome-wide occupancy of MEF2A and MEF2D in the presence or absence of one another. Although highly co-expressed in granule neurons, MEF2D is the predominant genomic regulator of gene expression. Strikingly, upon depletion of MEF2D, the occupancy of MEF2A robustly increases at a subset of sites normally bound to MEF2D. Epigenome and transcriptome analyses reveal that sites experiencing compensatory MEF2A occupancy undergo functional compensation for genomic activation and gene expression. In contrast, a distinct population of sites without compensatory MEF2A activity undergo significant dysregulation upon loss of MEF2D. The two populations of MEF2 target sites are further stratified by relative chromatin accessibility, with compensatory MEF2A activity concentrated within more open chromatin. Finally, we reveal that motor activity-induced changes in neuronal state induce a dynamic switch from non-compensatory to compensatory MEF2-dependent gene regulation, demonstrating the context-dependent nature of paralogous TF interdependency. Collectively, these studies define the first in vivo genome-wide characterization of functional interdependency between paralogous TFs.
2019-09-26 | GSE138028 | GEO
Project description:Chromatin environment and cellular context specify compensatory activity of paralogous MEF2 transcription factors
| PRJNA574197 | ENA
Project description:Compensation among paralogous transcription factors (TFs) confers genetic robustness of cellular processes, but how TFs dynamically respond to paralog depletion on a genome-wide scale in vivo remains incompletely understood. Using single and double conditional knockout of myocyte enhancer factor 2 (MEF2) family TFs in granule neurons of the mouse cerebellum, we find that MEF2A and MEF2D play functionally redundant roles in cerebellar-dependent motor learning. Although both TFs are highly expressed in granule neurons, transcriptomic analyses show MEF2D is the predominant genomic regulator of gene expression in vivo. Strikingly, genome-wide occupancy analyses reveal upon depletion of MEF2D, MEF2A occupancy robustly increases at a subset of sites normally bound to MEF2D. Importantly, sites experiencing compensatory MEF2A occupancy are concentrated within open chromatin and undergo functional compensation for genomic activation and gene expression. Finally, motor activity induces a switch from non-compensatory to compensatory MEF2-dependent gene regulation. These studies uncover genome-wide functional interdependency between paralogous TFs in the brain.
| S-EPMC6874310 | biostudies-literature
Project description:Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a novel mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine, and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine.
2008-08-24 | GSE11939 | GEO
Project description:Expression profiling in hippocampal neurons to identify genes upregulated in response to ectopic MEF2 activation by MEF2-VP16-ER Experiments were conducted to identify activity-regulated MEF2 target genes. Keywords: Gene activation time course
2009-01-12 | GSE13538 | GEO
Project description:Expression profiling in hippocampal neurons to identify activity-regulated genes controlled by MEF2 Experiments were conducted to identify activity-regulated MEF2 target genes. Keywords: Gene knockdown and depolarization time course
2009-01-12 | GSE13537 | GEO
Project description:Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a novel mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine, and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine. Mice were treated for 7 days with daily injections of cocaine (20 mg/kg) and sacrificed 24 hrs later. Chromatin from bilateral punches of NAc was immunoprecipitated with an antibody against MEF2A as described previously with minor modifications (Renthal et al., 2007). Chromatin was sonicated to an average of ~500 bp and immunoprepitated with antibody against MEF2A (Santa Cruz, sc-313) or an IgG control (Upstate/Millipore). Antibody-bound chromatin was precipitated using Protein A beads from Upstate (06-157), which were washed with low salt, high salt, and LiCl buffers to remove non-specific DNA binding. Eluted chromatin was reverse-crosslinked at 65oC in the presence of proteinase K and EDTA. DNA was purified by chloroform extraction/ethanol precipitation and the enrichment of specific promoters was amplified by ligation-mediated PCR for genome-wide analysis (Sikder et al., 2006). Amplified DNA was then labeled with Cy3 (input-enriched) or Cy5 (MEF2-enriched) and hybridized to Nimblegen (Madison, WI) MM8 mouse promoter arrays. Bilateral nucleus accumbens from eight mice were pooled for microarray analysis.
2008-08-24 | E-GEOD-11939 | biostudies-arrayexpress
Project description:BACKGROUND: The myocyte enhancer factor 2 (MEF2) gene family is broadly expressed during the development and maintenance of muscle cells. Although a great deal has been elucidated concerning MEF2 transcription factors' regulation of specific gene expression in diverse programs and adaptive responses, little is known about the origin and evolution of the four members of the MEF2 gene family in vertebrates. METHODOLOGY/PRINCIPAL FINDINGS: By phylogenetic analyses, we investigated the origin, conservation, and evolution of the four MEF2 genes. First, among the four MEF2 paralogous branches, MEF2B is clearly distant from the other three branches in vertebrates, mainly because it lacks the HJURP_C (Holliday junction recognition protein C-terminal) region. Second, three duplication events might have occurred to produce the four MEF2 paralogous genes and the latest duplication event occurred near the origin of vertebrates producing MEF2A and MEF2C. Third, the ratio (K(a)/K(s)) of non-synonymous to synonymous nucleotide substitution rates showed that MEF2B evolves faster than the other three MEF2 proteins despite purifying selection on all of the four MEF2 branches. Moreover, a pair model of M0 versus M3 showed that variable selection exists among MEF2 proteins, and branch-site analysis presented that sites 53 and 64 along the MEF2B branch are under positive selection. Finally, and interestingly, substitution rates showed that type II MADS genes (i.e., MEF2-like genes) evolve as slowly as type I MADS genes (i.e., SRF-like genes) in animals, which is inconsistent with the fact that type II MADS genes evolve much slower than type I MADS genes in plants. CONCLUSION: Our findings shed light on the relationship of MEF2A, B, C, and D with functional conservation and evolution in vertebrates. This study provides a rationale for future experimental design to investigate distinct but overlapping regulatory roles of the four MEF2 genes in various tissues.
| S-EPMC3048864 | biostudies-literature
Project description:Testosterone production by Leydig cells is a tightly regulated process requiring synchronized expression of several steroidogenic genes by numerous transcription factors. Myocyte enhancer factor 2 (MEF2) is a transcription factor recently identified in somatic cells of the male gonad. In other tissues, MEF2 is an essential regulator of organogenesis and cell differentiation. So far in the testis, MEF2 was found to regulate Leydig cell steroidogenesis by controlling Nr4a1 and Star gene expression. To expand our understanding of the role of MEF2 in Leydig cells, we performed microarray analyses of MA-10 Leydig cells depleted in MEF2 and results were analyzed using the Partek and IPA softwares. Several genes were differentially expressed in MEF2-depleted Leydig cells and 15 were validated by qPCR. A large number of these genes are known to be involved in fertility, gonad morphology and steroidogenesis and include Pde8a, Por, Ahr, Bmal1, Cyp1a1, Cyp1b1, Map2k1, Tsc22d3, Nr0b2, Smad4, and Star, which were all downregulated in the absence of MEF2. In silico analyses revealed the presence of MEF2 binding sites within the first 2 kb upstream the transcription start site of the Por, Bmal1, and Nr0b2 promoters, which suggests a direct regulation by MEF2. Using transient transfections in MA-10 Leydig cells, siRNA knockdown, and a MEF2-Engrailed dominant negative, we found that MEF2 activates the Por, Bmal1 and Nr0b2 promoters and that this requires an intact MEF2 element. Our results identify novel target genes for MEF2 and define MEF2 as an important regulator of Leydig cell function and male reproduction.
2015-04-12 | GSE64128 | GEO
Project description:The myogenic regulatory factor MRF4 is expressed at high levels in myofibers of adult skeletal muscle, but its function is unknown. Here we show that knockdown of MRF4 in adult muscle causes hypertrophy and prevents denervation-induced atrophy. This effect is accompanied by increased protein synthesis and the widespread activation of genes involved in muscle contraction, excitation-contraction coupling and energy metabolism, many of which are known targets of MEF2 transcription factors. Genes regulated by MEF2 represent the top-ranking gene set enriched after Mrf4 RNAi, and a MEF2 reporter is inhibited by co-transfected MRF4 and activated by Mrf4 RNAi. The role of MEF2 in mediating the effect of MRF4 knockdown is supported by the finding that Mrf4 RNAi-dependent increase in fiber size is prevented by dominant negative MEF2, while constitutively active MEF2 is able to induce myofiber hypertrophy. The nuclear localization of the MEF2 co-repressor HDAC4 is impaired by Mrf4 knockdown, suggesting that MRF4 acts by stabilizing a repressor complex that controls MEF2 activity. The demonstration that fiber size in adult skeletal muscle is controlled by the MRF4-MEF2 axis opens new perspectives in the search for therapeutic targets to prevent muscle wasting, in particular sarcopenia and cachexia.
2016-07-15 | GSE67069 | GEO