The Dlk1-Dio3 noncoding RNA cluster coordinately regulates mitochondrial respiration and chromatin structure to establish proper cell state for muscle differentiation.

Autor:	Pinheiro A; Program in Molecular Biology, Cell Biology, and Molecular Biology, Boston University, Boston, MA 02215, USA., Petty CA; Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, MA 02215, USA., Stephens CE; Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, MA 02215, USA., Cabrera K; Program in Molecular Biology, Cell Biology, and Molecular Biology, Boston University, Boston, MA 02215, USA., Palanques-Tost E; Bioinformatics Program, Boston University, Boston, MA 02215, USA., Gower AC; Clinical and Translational Science Institute, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA., Marano M; Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, MA 02215, USA., Leviss EM; Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, MA 02215, USA., Boberg MJ; Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, MA 02215, USA., Mahendran J; Bioinformatics Program, Boston University, Boston, MA 02215, USA., Bock PM; Bioinformatics Program, Boston University, Boston, MA 02215, USA., Fetterman JL; Department of Medicine, Vascular Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA., Naya FJ; Program in Molecular Biology, Cell Biology, and Molecular Biology, Boston University, Boston, MA 02215, USA.; Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, MA 02215, USA.
Jazyk:	angličtina
Zdroj:	Development (Cambridge, England) [Development] 2024 Dec 15; Vol. 151 (24). Date of Electronic Publication: 2024 Dec 20.
DOI:	10.1242/dev.203127
Abstrakt:	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. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2024. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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