Metabolic maturation during muscle stem cell differentiation is achieved by miR-1/133a-mediated inhibition of the Dlk-Dio3 mega gene cluster.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Thomas Boettger
PROVIDER: E-MTAB-5936 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:In placental mammals, adaptation to extra-uterine life requires complex metabolic adjustments linked to the abrupt transition from the transplacental transfer of glucose toward the use of fat originating from the motherM-bM-^@M-^Ys milk as a major energy source. The study of a novel knock-out mouse model led us to identify the biological roles of the miR-379/miR-410 cluster at the imprinted Dlk1-Dio3 region during this metabolic transition. The miR-379/miR-410 cluster is the largest mammalian-specific miRNA cluster composed of 39 pre-miRNA and expressed from the maternally-inherited allele. We unexpectedly found that ~ 35% of heterozygous neonates with a maternal - but not paternal - deletion of the entire 40kb-long miRNA cluster die shortly after birth due to defects in the maintenance of energy homeostasis, as evidenced by impaired hepatic glycogenolysis, gluconeogenesis and ketogenesis. This maladaptive metabolic response is accompanied by profound changes in the neonatal hepatic gene expression program, notably a decrease in the activation of a large set of metabolic genes linked to lipid metabolism. Our study unveils essential roles for the miR-379/miR-410 cluster at the transition from fetal to postnatal life, revealing new layers of RNA-mediated gene regulation at the Dlk1-Dio3 domain that impose parent-of-origin effects on postnatal metabolic functions. Liver gene expression was measured in mice with a maternally-inherited deletion of the miR-379/miR-410 cluster and in wild-type littermates at embryonic day E19.5, 4h following the caesarean delivery (n=4 biological replicates per genotype)
2014-08-22 | E-GEOD-47155 | biostudies-arrayexpress
Project description:In placental mammals, adaptation to extra-uterine life requires complex metabolic adjustments linked to the abrupt transition from the transplacental transfer of glucose toward the use of fat originating from the motherM-bM-^@M-^Ys milk as a major energy source. The study of a novel knock-out mouse model led us to identify the biological roles of the miR-379/miR-410 cluster at the imprinted Dlk1-Dio3 region during this metabolic transition. The miR-379/miR-410 cluster is the largest mammalian-specific miRNA cluster composed of 39 pre-miRNA and expressed from the maternally-inherited allele. We unexpectedly found that ~ 35% of heterozygous neonates with a maternal - but not paternal - deletion of the entire 40kb-long miRNA cluster die shortly after birth due to defects in the maintenance of energy homeostasis, as evidenced by impaired hepatic glycogenolysis, gluconeogenesis and ketogenesis. This maladaptive metabolic response is accompanied by profound changes in the neonatal hepatic gene expression program, notably a decrease in the activation of a large set of metabolic genes linked to lipid metabolism. Our study unveils essential roles for the miR-379/miR-410 cluster at the transition from fetal to postnatal life, revealing new layers of RNA-mediated gene regulation at the Dlk1-Dio3 domain that impose parent-of-origin effects on postnatal metabolic functions. Liver gene expression at P1 was measured in neonates with a maternally-inherited deletion of the miR-379/miR-410 cluster (KO) and compared to that of wild-type littermates (n=5). KO_normoglycemic and KO_hypoglycemic individuals correspond to mutant pups wild mild hypoglycemia (n=3) and with severe hypoglycemia (n =7), respectively.
2014-08-22 | E-GEOD-57112 | biostudies-arrayexpress
Project description:In placental mammals, adaptation to extra-uterine life requires complex metabolic adjustments linked to the abrupt transition from the transplacental transfer of glucose toward the use of fat originating from the motherM-bM-^@M-^Ys milk as a major energy source. The study of a novel knock-out mouse model led us to identify the biological roles of the miR-379/miR-410 cluster at the imprinted Dlk1-Dio3 region during this metabolic transition. The miR-379/miR-410 cluster is the largest mammalian-specific miRNA cluster composed of 39 pre-miRNA and expressed from the maternally-inherited allele. We unexpectedly found that ~ 35% of heterozygous neonates with a maternal - but not paternal - deletion of the entire 40kb-long miRNA cluster die shortly after birth due to defects in the maintenance of energy homeostasis, as evidenced by impaired hepatic glycogenolysis, gluconeogenesis and ketogenesis. This maladaptive metabolic response is accompanied by profound changes in the neonatal hepatic gene expression program, notably a decrease in the activation of a large set of metabolic genes linked to lipid metabolism. Our study unveils essential roles for the miR-379/miR-410 cluster at the transition from fetal to postnatal life, revealing new layers of RNA-mediated gene regulation at the Dlk1-Dio3 domain that impose parent-of-origin effects on postnatal metabolic functions. Liver gene expression was measured in mice with a maternally-inherited deletion of the miR-379/miR-410 cluster (KO) and in wild-type littermates (WT) at embryonic day E19.5 (n=3 per genotype) and on the day of birth (P0, n=4 WT and 5 KO).
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Project description:We identified genes expressed in mouse skeletal muscle, during the process of muscle regeneration after injury, which are dysregulated in the absence of Mef2a expression. MEF2A is a member of the evolutionarily conserved MEF2 transcription factor family which has known roles in cardiac muscle development and function, but is not well studied in skeletal muscle. We performed a comparison of gene expression profiles in wild type and MEF2A knockout tibialis anterior muscle, seven days post-injury with cardiotoxin. The results indicated that a variety of genes expressed during muscle regeneration, predominantly microRNAs in the Gtl2-Dio3 locus, are dysregulated by the loss of MEF2A expression.
2013-02-12 | GSE41871 | GEO
Project description:We identified genes expressed in mouse skeletal muscle, during the process of muscle regeneration after injury, which are dysregulated in the absence of Mef2a expression. MEF2A is a member of the evolutionarily conserved MEF2 transcription factor family which has known roles in cardiac muscle development and function, but is not well studied in skeletal muscle. We performed a comparison of gene expression profiles in wild type and MEF2A knockout tibialis anterior muscle, seven days post-injury with cardiotoxin. The results indicated that a variety of genes expressed during muscle regeneration, predominantly microRNAs in the Gtl2-Dio3 locus, are dysregulated by the loss of MEF2A expression. Skeletal muscle RNA used in the present study included the following two sample groups: (WT) pooled total RNA from tibialis anterior muscle taken from 5 wild type mice at seven days post-injury with 10uM cardiotoxin; (KO) pooled total RNA from tibialis anterior muscle taken from 5 Mef2a knockout mice at seven days post-injury with 10uM cardiotoxin. All mice were between 2-4 months of age. Both male and female mice were used.
2013-02-12 | E-GEOD-41871 | biostudies-arrayexpress
Project description:To detect the effect of early culture on hESCs, almost all initial-passaged hESCs have normal expression of DLK1-DIO3 gene cluster, the low-passaged hESCs lost the expression of DLK1-DIO3 gene cluster.
2014-06-30 | GSE38662 | GEO
Project description:To detect the effect of early culture on hESCs, almost all initial-passaged hESCs have normal expression of DLK1-DIO3 gene cluster, the low-passaged hESCs lost the expression of DLK1-DIO3 gene cluster. hESCs were extracted for RNA with TriZOL and hybridization on Affymetrix arrays
2014-06-30 | E-GEOD-38662 | biostudies-arrayexpress
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.
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Project description:The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, sug- gesting a role for β-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and β-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds.
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