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Chromatin Accessibility Analysis Reveals Distinct Functions for HDAC and EZH2 Activities in Early Regeneration

ABSTRACT: Xenopus tropicalis tadpoles have the capability to scarlessly regenerate appendages including the limb and tail. Following injury, complex genetic processes must be activated and inactivated with high spatial and temporal resolution to result in a properly patterned appendage. Functional studies have established that histone modifying enzymes that act to close chromatin are required for regeneration, but the genomic regions sensitive to these activities are not established. Here we show that early inhibition of HDAC or Ezh2 activity results in incomplete regeneration. To identify the impact that each of these perturbations has on chromatin accessibility, we applied an assay for transposase accessible chromatin (ATAC-seq) to HDAC or Ezh2 inhibited regenerating tadpoles. We find that neither perturbation results in a global increase in chromatin accessibility, but that both inhibitors have targeted effects on chromatin accessibility and gene expression. Upon HDAC inhibition, promoter regions and regulatory regions neighboring genes associated with neuronal regeneration are precociously accessible, whereas following EZH2 inhibition we find gene bodies and regulatory regions associated with regulation of the immune response and apoptosis are preferentially accessible. Together this suggests distinct roles for EZH2 activity and HDAC activity in appendage regeneration.

ORGANISM(S): Xenopus tropicalis

PROVIDER: GSE175662 | GEO | 2022/05/01

REPOSITORIES: GEO

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Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration M-bM-^@M-^S is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an M-bM-^@M-^\HDAC-myomiR-BAF60 variant networkM-bM-^@M-^] regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a M-bM-^@M-^\latentM-bM-^@M-^] myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) 1.2, 133 and 206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. Genome-wide chromatin accessibility patterns in FAPs cells derived from mdx mice at different ages treated either with HDAC inhibitor Trichostatin A (TSA) or with vehicle (saline solution) were assessed using NA-seq (PMID: 19289091)

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Chromatin Accessibility Analysis Reveals Distinct Functions for HDAC and EZH2 Activities in Early Regeneration

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