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ChIP-seq profiling of transcriptional co-activator p300 during early myogenic differentiation

ABSTRACT: Molecular regulation of stem cell differentiation is exerted through both genetic and epigenetic determinants over distal regulatory or enhancer regions. Understanding the mechanistic action of active or poised enhancers is thus imperative for control of stem cell differentiation. Based on a genome-wide co-occurrence of different epigenetic marks in committed proliferating myoblasts, we have previously generated a 14-state chromatin state model to profile residue-specific histone acetylation in early myoblast differentiation. Here, we use genome-wide chromatin state association to delineate the functional mode of transcription regulators in early myogenic differentiation. We define a role of transcriptional coactivator p300, when recruited by master muscle regulator MyoD, in the establishment and regulation of myogenic loci at the onset of terminal differentiation. In addition, we reveal an enrichment of residue- and loci-specific histone acetylation at p300 associated active or poised enhancers, particularly when enlisted by MyoD. We provide novel molecular insights into the regulation of myogenic enhancers by p300 in concert with MyoD. Our studies present a valuable aptitude for driving stage specific chromatin state or enhancers pharmacologically to treat muscle related diseases and for the identification of additional myogenic targets and molecular interactions for therapeutic development.

ORGANISM(S): Mus musculus

PROVIDER: GSE109636 | GEO | 2018/07/30

REPOSITORIES: GEO

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Project description:Background: Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was sufficient to induce differentiation and suppress multiple growth-promoting genes, suggesting that the dimer was targeting a switch that regulated the transition from growth to differentiation. Our data also suggested that a balance existed between various inhibitory transcription factors and MyoD activity that kept rhabdomyosarcomas trapped in a proliferative state. Methods: Potential myogenic co-factors identified by analysis of high-throughput sequencing of chromatin immunoprecipitation experiments in normal myogenic cells were tested for their ability to drive differentiation in rhabdomyosarcoma cell culture models, and their relation to MyoD activity determined through molecular biological experiments. Results: Modulation of the transcription factors RUNX1 and ZNF238, factors with poorly delineated roles in myogenic development, can induce differentiation in rhabdomyosarcoma cells and their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation. The inhibitory transcription factor MSC also plays a role in controlling miR-206, appearing to function by occluding a binding site for MyoD in the miR-206 promoter. Conclusions: These findings suggest that nested feed-forward circuits that proceed from MyoD, to RUNX1, to ZNF238, and finally to miR-206 function in both rhabdomyosarcomas as well as normal myogenesis to control the decision point of proliferation versus differentiation. Total RNA samples were collected from human RD cells transduced with lentivirus carrying RUNX1, RP58 (ZNF238), miR-206 or GFP (three biological replicates each) and allowed to differentiate for 72 hours.

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ChIP-seq profiling of transcriptional co-activator p300 during early myogenic differentiation

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