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The mRNA-binding proteome of proliferating and differentiated muscle cells

ABSTRACT: Muscle formation is a coordinated process driven by extensive gene expression changes where single cells fuse together to form multinucleated muscle fibers. Newly synthesized mRNAs are then regulated by RNA binding proteins(RBPs)affecting post-transcriptional transcripts metabolism. We determined how large gene expression changes affect the catalog of RBPs by studying proliferating and differentiated muscle cells in healthy and dystrophic conditions. Transcriptomic analysis showed that the expression of more than 7000 genes was affected during myogenesis. We identified 769 RBPs, of which 294 were muscle specific and 49 were uniquely shared with cardiomyocytes. A subset of 32 RBPs (half of which was muscle specific) showed preferential loading on target mRNAs in either myoblasts or myotubes. A large proportion of catalytic proteins was bound to mRNAs even though they lack classical RNA binding domains. Finally we show how the identification of cell specific RBPs enabled the identification biomarkers that can separate healthy individuals from dystrophic patients. Our data show how interactome data can shed light on new basic RNA biology as well as provide cell specific data that can be used for diagnostic purposes.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Duchenne Muscular Dystrophy

SUBMITTER: G Janssen

LAB HEAD: P.A.van Veelen

PROVIDER: PXD015471 | Pride | 2020-06-09

REPOSITORIES: Pride

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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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The mRNA-binding proteome of proliferating and differentiated muscle cells

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