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MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers (ChIP-Seq)

ABSTRACT: Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites, and redirects it to retina-specific enhancers that lack the consensus MEF2 sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs, and through cooperative activation of these enhancers to regulate tissue-specific genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE61391 | GEO | 2015/03/19

SECONDARY ACCESSION(S): PRJNA260927

REPOSITORIES: GEO

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MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers (RNA-Seq)

Project description:Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites, and redirects it to retina-specific enhancers that lack the consensus MEF2 sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs, and through cooperative activation of these enhancers to regulate tissue-specific genes.

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MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers

Project description:MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers

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MEF2D binding sites in rat hippocampal neurons

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Information Content Differentiates Enhancers From Silencers in Mouse Photoreceptors

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Project description:Many transcription factors regulating the production, survival and function of photoreceptor cells in the retina have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here we show that BCL6 co-repressor (BCOR), a polycomb repressive complex I factor mutated in various cancers, negatively regulates photoreceptor gene expression. Using proteomics and promoter assays, we find that BCOR interacts with the photoreceptor transcription factors OTX2 and CRX, and reduces their ability to activate the promoters of photoreceptor-specific genes, such as Rhodopsin and Nrl. CUT&RUN sequencing further shows that BCOR shares genome-wide binding profiles with CRX/OTX2, consistent with a general co-repression activity. Finally, we identify missense variants in the human BCOR gene in six families with early-onset X-linked inherited retinal degeneration (IRD). Together, this work uncovers BCOR as a co-repressor of OTX2/CRX essential for photoreceptor cell biology and survival.

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Chromatin environment and cellular context specify compensatory activity of paralogous MEF2 transcription factors

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.

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