Dataset Information

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

ABSTRACT: The coordinate regulation of metabolic activity and epigenetics to establish cell state-specific gene expression patterns during lineage progression is among the most important aspects of cell differentiation. Cell states are defined by their epigenetic landscape and have cell state-specific metabolic demands. Defining the regulatory factors involved in the interplay between metabolism and cell state would represent a significant step forward in understanding the genetic circuitry that drives differentiation of progenitor cells into highly specialized cell types for proper tissue formation. Expression levels of the imprinted Dlk1-Dio3 noncoding RNA (ncRNA) mega-cluster have been shown to correlate with distinct metabolic profiles in a variety of progenitor cells, suggesting it functions as a key regulator of metabolism and cell state. Here, we directly demonstrate that the Dlk1-Dio3 ncRNA locus is a central player coordinating mitochondrial metabolic activity and genome-wide epigenetic changes in myoblasts and differentiated myotubes. Stable muscle cell lines were generated harboring two distinct deletions in the proximal promoter region resulting in either greatly upregulated or severely attenuated transcription of the entire mega-cluster of Dlk1-Dio3 ncRNAs. Both mutant lines displayed impaired myotube formation along with perturbed mitochondrial respiration and widespread changes in chromatin accessibility and histone methylation. Global gene expression patterns and pathway analyses indicated a reprogramming of cell state which created a differentiated-like molecular profile in proliferating myoblasts. Our results strongly suggest that the Dlk1-Dio3 ncRNA locus is a nodal regulator coordinating metabolic activity and the epigenome to maintain proper cell state in the myogenic lineage.

ORGANISM(S): Mus musculus

PROVIDER: GSE268482 | GEO | 2024/12/04

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Our previous study demonstrated a significant upregulation of a large set of miRNAs at the genomic imprinted Dlk1-Dio3 locus in lymphocytes of diverse murine lupus-prone strains. The upregulation of Dlk1-Dio3 miRNAs in lupus-prone mice is correlated with the global DNA hypomethylation. In this study, by performing genome-wide DNA methylation analysis, we reported that Dlk1-Dio3 genomic region in CD4+ T cells of MRL/lpr mice was hypomethylated, further linking hypomethylation to the increased expression of Dlk1-Dio3 miRNAs in lupus. Then, we assessed the gene expression levels of enzymes that either write (DNA methyltransferases, DNMTs) or erase DNA methylation (Ten-eleven translation proteins, TETs) to understand the molecular contributor to the DNA hypomethylation in MRL/lpr CD4+ T cells. The expression levels of Dnmt1, Dnmt3b, Tet1, and Tet2 were significantly increased in CD4+ T cells of MRL/lpr mice, as well as in B6/lpr and B6.sle123 mice, compared to their respective control mice. These data indicate the significant involvement of the TETs-mediated active demethylation pathway rather than reduced DNMTs-mediated passive demethylation pathway in the hypomethylation of murine lupus CD4+ T cells. The transcription factor, early growth response 2 (EGR2) is critically involved in regulating T cell functions and autoimmunity. In this research, we found that Egr2 deletion in B6/lpr mice notably reduced methylation-sensitive Dlk1-Dio3 cluster miRNAs expression in CD4+ T cells. Surprisingly, even though EGR2 has been shown to induce DNA demethylation by recruiting TET2, we found that deleting Egr2 in B6/lpr mice induced a higher number of hypomethylated DMRs than hypermethylated DMRs at either whole genome or the Dlk1-Dio3 locus in CD4+ T cells of B6/lpr mice. These data are the first finding on the positive role of EGR2 on the expression of Dlk1-Dio3 cluster miRNAs in lupus mice. Given that Dlk1-Dio3 miRNAs target the major signaling pathways in autoimmunity, these data provide a new perspective in understanding the potential pathogenic role of upregulated EGR2 in lupus.

Dataset Information

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

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets