The coordinate regulation of metabolism and epigenetics to establish cell state-specific gene expression patterns during lineage progression is a central aspect of cell differentiation, but the factors that regulate this elaborate interplay are not well-defined. The imprinted Dlk1-Dio3 noncoding RNA (ncRNA) cluster has been associated with metabolism in various progenitor cells, suggesting it functions as a regulator of metabolism and cell state. Here, we directly demonstrate that the Dlk1-Dio3 ncRNA cluster coordinates mitochondrial respiration and chromatin structure to maintain proper cell state. Stable mouse muscle cell lines were generated harboring two distinct deletions in the proximal promoter region, resulting in either greatly upregulated or downregulated expression of the entire Dlk1-Dio3 ncRNA cluster. Both mutant lines displayed impaired muscle differentiation along with dysregulated structural gene expression and abnormalities in mitochondrial respiration. Genome-wide chromatin accessibility and histone methylation patterns were also severely affected in these mutants. Our results strongly suggest that muscle cells are sensitive to Dlk1-Dio3 ncRNA dosage, and that the cluster coordinately regulates metabolic activity and the epigenome to maintain proper cell state in the myogenic lineage.

Keywords:
Muscle differentiation, Mitochondria, Epigenetics, Dlk1-Dio3, Noncoding RNA

Author contributions

Conceptualization: A.P., C.A.P., F.J.N.; Methodology: A.P., C.A.P., M.M., E.M.L., M.J.B., J.L.F.; Formal analysis: A.P., M.M., E.M.L., M.J.B., J.M., P.M.B.; Investigation: A.P., C.A.P., M.M., E.M.L., M.J.B., F.J.N.; Data curation: A.P., C.E.S., K.C., E.P.-T., A.C.G., J.M., P.M.B.; Writing - original draft: A.P., F.J.N.; Writing - review & editing: A.P., F.J.N.; Visualization: C.E.S., K.C., E.P.-T., A.C.G.; Supervision: J.L.F., F.J.N.; Project administration: F.J.N.; Funding acquisition: F.J.N.

Funding

This work was supported by a GSI Pilot Grant Award from The Genome Science Institute at Boston University Chobanian and Avedisian School of Medicine, and by funds provided by Boston University.

Data availability

The RNA-seq data have been deposited in GEO under accession number GSE268482. The CUT&RUN data have been deposited in GEO under accession number GSE272974. The ATAC-seq data have been deposited in GEO under accession number GSE284208.

The people behind the papers

This article has an associated ‘The people behind the papers’ interview with some of the authors.

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2024
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