Constitutive loss of DNMT3A causes morbid obesity through misregulation of adipogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA692391 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13443234_1.fastq.gz | Fastqsanger.gz | |||
| SRR13443234_2.fastq.gz | Fastqsanger.gz | |||
| SRR13443235_1.fastq.gz | Fastqsanger.gz | |||
| SRR13443235_2.fastq.gz | Fastqsanger.gz | |||
| SRR13443236_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:DNA Methyltransferase 3A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.
2022-05-10 | GSE164892 | GEO
Project description:DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.
| S-EPMC9150890 | biostudies-literature
Project description:Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that is proposed to function as a transcriptional repressor, but, despite numerous studies examining neuronal gene expression in MeCP2 mutants, no coherent model has emerged for how MeCP2 regulates transcription. Here we identify a genome-wide length-dependent increase in the expression of long genes in neurons lacking MeCP2. This gene misregulation occurs in human RTT brains and correlates with onset and severity of phenotypes in Mecp2 mutant mice, suggesting that the disruption of long gene expression contributes to RTT pathology. We present evidence that MeCP2 represses long genes by binding to brain-enriched, methylated CA dinucleotides within genes and show that loss of methylated CA in the brain recapitulates gene expression defects observed in MeCP2 mutants. We find that long genes encode proteins with neuronal functions, and overlap substantially with genes that have been implicated in autism and Fragile X syndrome. Reversing the overexpression of long genes in neurons lacking MeCP2 can improve some RTT-associated cellular deficits. These findings suggest that a function of MeCP2 in the mammalian brain is to temper the expression of genes in a length-dependent manner, and that mutations in MeCP2 and possibly other autism genes may cause neurological dysfunction by disrupting the expression of long genes in the brain.
2015-03-12 | GSE60070 | GEO
Project description:RNASeq of K562 cell clones for DNMT3A-WT, DNMT3A-W305*, DNMT3A-R882H, DNMT3A-R882C
| PRJNA1221929 | ENA
Project description:DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns, essential for the dynamic organization of vertebrate genomes. However, the mechanisms underlying DNMT3A1's recruitment and function within different chromatin environments remain unclear. We find that DNMT3A interacts with modified nucleosomes through multivalent interactions, involving both direct binding to chromatin features and site-specific post-translational histone modifications.
2024-12-07 | PXD046529 | Pride
Project description:We characterized the role of the DNA methyltransferase DNMT3A in the fate decisions of murine megakaryocyte-biased HSCs and in the differentiation of megakaryocytes and platelets. In this experiment, we isolated washed platelets from 4 WT and 4 Dnmt3a+/– germline mice (2 males and 2 females per group) and subjected them to proteomic analysis by mass-spectrometry. We sought to identify changes at the protein level that occur in platelets due to aberrant DNA methylation during the differentiation of upstream hematopoietic cells.
2025-06-09 | PXD055265 | Pride
Project description:DNMT3A (which encodes a de novo DNA methyltransferase) is one of the most frequently mutated genes in AML genomes. Point mutations at position R882 have been shown to cause a dominant negative loss of DNMT3A methylation activity, but 15% of DNMT3A mutations are predicted to produce truncated proteins, which could either have dominant negative activities, or cause loss-of-function and haploinsufficiency. We demonstrate that three of these mutants produce truncated, inactive proteins that do not dimerize with wild-type DNMT3A, strongly supporting the haploinsufficiency hypothesis. We therefore evaluated hematopoiesis in mice heterozygous for a constitutive null Dnmt3a mutation: unmanipulated mice developed myeloid skewing over time, and their stem/progenitor cells exhibited a long-term competitive transplantation advantage. Dnmt3a+/- mice spontaneously developed transplantable myeloid malignancies after a long latent period, and three of 12 tumors tested had cooperating mutations in the Ras- MAPK pathway. The residual Dnmt3a allele was neither mutated nor downregulated in tumors. The bone marrow cells of Dnmt3a+/- mice had a subtle but significant DNA hypomethylation phenotype that was not associated with gene dysregulation. These data demonstrate that haploinsufficiency for DNMT3A alters hematopoiesis, and predisposes mice (and probably humans) to myeloid malignancies by a mechanism that is not yet clear.
2017-08-01 | GSE100702 | GEO
Project description:Maintenance of human pluripotent stem cells is dependent on extrinsic signals and cross talk between transcriptional and epigenetic regulators. Methylation of cytosines through the de novo methyltransferases DNMT3A and 3B plays an important role for exiting pluripotency and facilitating proper differentiation. Here, we generated and analyzed single cell expression data from wild-type and DNMT3A/B knockout human embryonic stem cells to better understand the precise effects on pluripotency and differentiation. Although DNA methylation is generally associated with gene silencing, we find unexpected and widespread transcriptional repression upon loss of DNMT3A or DNMT3A/3B. Furthermore, the transcriptional misregulation in DNMT3A knockout cells is largely propagated during differentiation towards mesoderm. Additionally, we observe increased cellular and transcriptional heterogeneity in undifferentiated cells upon deactivation of DNMTs as well as a notable change in cell cycle gene expression. Taken together, our single-cell RNA sequencing data provides several new insights into the role of DNA methylation in human pluripotent stem cells.
2019-08-30 | GSE134483 | GEO
Project description:Transcriptional profiling of mouse lung tumors comparing Dnmt3a KO/K-ras G12D mutant with Dnmt3a WT/K-ras G12D mutant. The goal is to search for the difference of mRNA abundance between Dnmt3a KO and WT tumors. Two-condition experiment, KO vs. WT tissure. Biological replicates: 12.
2011-10-25 | E-GEOD-32415 | biostudies-arrayexpress
Project description:This study was carried out to determine how immunological signatures related in the colon and periperhal blood between indivudals with Crohn's, Spondyloarhtritis, and individuals with both diseases. We carried out one experiments with 1 patient in each condition (1 Crohn's, 1 Spondyloarthritis, 1 Co-morbid, 1 HC), which we then repeated for a total of 8 subjects.
2021-05-25 | GSE163314 | GEO