Cell differentiation involves crosstalk between metabolism and epigenetics to establish specific gene expression patterns during lineage progression. One candidate regulator in this interplay is the Dlk1-Dio3 noncoding RNA (ncRNA) locus, which encodes three different classes of ncRNAs and spans over 200 kilobases, making it challenging to investigate the function of the whole cluster. In this new study, Francisco Naya and colleagues find that the Dlk1-Dio3 ncRNA locus is a regulator of cell state in muscle cell lines and is necessary for proper skeletal muscle differentiation. First, they generate two muscle cell lines with distinct deletions in the proximal promoter region of the Dlk1-Dio3 ncRNA cluster, resulting in either upregulation or downregulation of the entire cluster. Both mutant lines display impaired muscle differentiation and dysregulated gene expression. Then, the authors observe that many genes involved in oxidative phosphorylation are strongly dysregulated in both lines. Furthermore, mitochondrial respiration activity is sensitive to Dlk1-Dio3 ncRNA dosage. Finally, ATAC-seq and CUT&RUN sequencing reveal genome-wide changes in chromatin accessibility and histone methylation patterns in both lines, resulting in altered cell state. In sum, the findings suggest that the Dlk1-Dio3 ncRNA locus regulates cell state by coordinating mitochondrial activity and histone modifications in muscle cells.
