Epigenetic and transcriptomic alterations in Dnmt3a mutants
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PROVIDER: PRJEB78856 | ENA |
REPOSITORIES: ENA
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Project description:Tissue-Biased Expansion of DNMT3A-Mutant Clones Associated with Conserved Epigenetic Alterations
| PRJNA632619 | ENA
Project description:DNA methyltransferase 3A (DNMT3A) is the most frequently mutated gene in clonal hematopoiesis (CH) and serves as a key tumor suppressor in the hematopoietic system. Somatic mutations in DNMT3A arise in hematopoietic stem and progenitor cells (HSPCs) many years before malignancies develop, but how they prime cells for transformation remains unknown, partly due to our inability to compare mutant to equivalent wild-type cells before frank disease. To overcome this challenge, we derived multiple normal and DNMT3A-mutant lymphoblastoid cell clones from a germ-line mosaic individual in whom these cells co-existed for nearly six decades. Although arising early in gestation, mutant cells dominated the blood, but not other tissues. Deep sequencing revealed similar mutational burdens and mutational signatures across normal and mutant clones. In contrast, epigenetic profiling uncovered focal erosion of DNA methylation at oncogenic regulatory regions in mutant clones. These regions overlapped with those sensitive to DNMT3A loss after DNMT3A ablation in HSPCs and with those present in leukemia samples. These results suggest that DNMT3A is responsible for maintaining a conserved DNA methylation pattern that is maintained for decades and across cell types and states. Erosion of this pattern confers a distinct competitive advantage, increasing the likelihood of malignant transformation
2020-07-15 | GSE150515 | GEO
Project description:Transcriptomic and epigenetic disruptions in excitatory neurons in Dnmt3a conditional knockout mouse
| PRJNA594019 | ENA
Project description:DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that DNMT3A mutational hotspot at Arg882 (DNMT3A R882H) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3A R882H directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1 and Hoxa gene cluster. DNMT3A R882H induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3A R882H-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3A R882H-induced gene expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias. This SuperSeries is composed of the SubSeries listed below.
2016-06-23 | GSE71475 | GEO
Project description:Phenotypic heterogeneity in monogenic neurodevelopmental disorders can arise from differential severity of variants underlying disease, but how distinct alleles drive variable disease presentation is not well understood. Here, we investigate missense mutations in DNMT3A, a DNA methyltransferase associated with overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity. We generate a DNMT3A P900L/+ mouse mimicking a mutation with mild-to-moderate severity, and compare phenotypic and epigenomic effects with a severe R878H mutation. P900L mutants exhibit core growth and behavioral phenotypes shared across models but show subtle epigenomic changes, while R878H mutants display extensive disruptions. We identify mutation-specific dysregulated genes which may contribute to variable disease severity. Shared transcriptomic disruption identified across mutations overlaps dysregulation observed in other developmental disorder models and likely drives common phenotypes. Together, our findings define central drivers of DNMT3A disorders and illustrate how variable epigenomic disruption contributes to phenotypic heterogeneity in neurodevelopmental disease.
2023-11-08 | GSE225372 | GEO
Project description:We created a mouse line in which deletion of exon 19 of Dnmt3a is driven by the Neurod6 promoter (also known as Nex-Cre line). In this conditional knockout (cKO), Dnmt3a is functionally ablated in excitatory neurons in the neocortex and hippocampus starting in mid/late gestation (~E13-15). With an affinity purification approach to isolate tagged nuclei in mice (similar to INTACT; [Deal R.B. and Henikoff S. A simple method for gene expression and chromatin profiling of individual cell types within a tissue. Dev. Cell 18,1030-1040. (2010)]), we characterized the genome-wide patterns of transcription, DNA methylation, and histone modifications in excitatory pyramidal neurons of the frontal cortex from the Dnmt3a cKO and control mice. Our data provide a detailed assessment of the molecular basis of the accompanying changes of neurophysiological and behavioral phenotypes in the cKO mice, and suggest a complex interaction between DNA methylation and Polycomb-mediated repression in the epigenetic regulation in developing brain cells.
2022-05-23 | GSE141587 | GEO
Project description:During differentiation, neurons experience a reorganization of DNA modification patterns within their genomes. However, the mechanisms underlying this developmental patterning and its role in defining the neuronaÂÂl state are currently unclear. Here, we find that the dÂÂe novo DNA methyltransferase Dnmt3a is necessary for elevated levels of 5-hydroxymethylcytosine (5hmC), a derivative of 5-methylcytosine (5mC), in olfactory sensory neurons (OSNs). Through an analysis of genome-wide 5mC and 5hmC distributions in isolated OSNs, we find that Dnmt3a-dependent 5mC and 5hmC occurs within regions of high accessibility, neural enhancers, and the transcription start sites of transcribed genes. Its loss results in the global disruption of gene expression patterns, including the upregulation of silent genes, the downregulation of mOSN-expressed genes, and the alteration of odorant-induced transcriptional responses of immediate early genes. Together, these results demonstrate that Dnmt3a is necessary to define the neuronal transcriptional state and may be broadly involved in refining expression profiles within differentiated cells. To determine the contributions of Dnmt3a to the DNA modification and transcriptional landscapes of a post-mitotic neuronal population, we performed DNA immunoprecipitation (DIP-seq) using antibodies specific for 5mC and 5hmC and rRNA-depleted transcriptional profiling (RNA-seq) coupled to high-throughput sequencing using genomic DNA or RNA from FACS-isolated mature olfactory sensory neurons (mOSNs) from main olfactory epithelium (MOE) of Dnmt3a wildtype (WT), heterozygous-null (Het), or homozygous-null (KO) 3-week old mice. Similarly, to compare this information with other epigenetic features of the MOE, we performed H3K4me1 (WT), H3K27ac (WT), and H3K27me3 (WT and KO) chromatin immunoprecipitation (ChIP)-seq and DNase I hypersensitivity assays (DNase-seq) using MOE nuclei from 3-week old mice. In addition, we assayed the influence of Dnmt3a-deficiency on the induction of odorant-responsive genes by exposing 3-week old Dnmt3a WT, Het, and KO mice to either water or a 1:1:1 mixture of amyl acetate:acetophenone:octanal for 1 hour and performed rRNA-depleted RNA-seq using RNA isolated from their MOEs.
2014-11-05 | E-GEOD-52464 | biostudies-arrayexpress
Project description:Transcriptomic analysis of HepG2 cells overexpressing DNMT3A
| PRJNA1198943 | ENA
Project description:Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are associated with adverse prognosis in patients with heart failure (HF). The interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential interaction partners of CHIP-mutated monocytes using combined transcriptomic data from peripheral blood mononuclear cells of HF patients with and without CHIP and cardiac tissue. We demonstrate that DNMT3A inactivation augments macrophage-to-cardiac fibroblasts interactions and induces cardiac fibrosis in mice and humans. Mechanistically, DNMT3A inactivation increases the release of heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) to activate cardiac fibroblasts. These findings not only identify a novel pathway of DNMT3A CHIP-driver mutation-induced instigation and progression of HF, but may also provide a rationale for the development of new anti-fibrotic strategies.
2023-10-20 | E-MTAB-13384 | biostudies-arrayexpress
Project description:DNA methyltransferases DNMT3A- and DNMT3B-mediated de novo DNA methylation critically regulates epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote macro-oligomer formation, leading to aberrant DNA methylation that in turn contributes to pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the hotspot mutation-induced functional mis-regulation of DNMT3A remains unclear. Here, we report the crystal structure of DNMT3A methyltransferase (MTase) domain, revealing a molecular basis for its DNMT3B-distinct oligomerization behavior. Introducing DNMT3B-converting mutations to DNMT3A R882 mutants also led to structure determination of R882H- and R882C-mutated DNMT3A, which show enhanced intermolecular contacts than wild-type DNMT3A. Consistently, our in vitro and genomic DNA methylation analyses reveal that the DNMT3B-converting mutations eliminate the gain-of-function effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutation-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.
2023-12-31 | GSE225828 | GEO