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Variants of DNMT3A cause transcript-specific DNA methylation and gene expression changes

ABSTRACT: Variants of DNMT3A cause transcript-specific DNA methylation and gene expression changes

PROVIDER: PRJNA399744 | ENA |

REPOSITORIES: ENA

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Variants of DNMT3A cause transcript-specific DNA methylation changes

Project description:The de novo DNA methyltransferase 3A (DNMT3A) plays a pivotal role in hematopoietic differentiation. In this study, we followed the hypothesis that alternative splicing of DNMT3A has characteristic epigenetic and functional sequels. Various transcripts of DNMT3A were either knocked down or overexpressed in human hematopoietic stem and progenitor cells resulting in complementary and transcript-specific DNA methylation (DNAm) and gene expression changes. Our results demonstrate that different splice variants of DNMT3A have distinct epigenetic and functional sequels.

2018-12-10 | GSE103006 | GEO

Variants of DNMT3A cause transcript-specific gene expression changes

2018-12-10 | GSE103007 | GEO

Variants of DNMT3A cause transcript-specific DNA methylation patterns and affect hematopoiesis.

Project description:De novo DNA methyltransferase 3A (DNMT3A) plays pivotal roles in hematopoietic differentiation. In this study, we followed the hypothesis that alternative splicing of DNMT3A has characteristic epigenetic and functional sequels. Specific DNMT3A transcripts were either down-regulated or overexpressed in human hematopoietic stem and progenitor cells, and this resulted in complementary and transcript-specific DNA methylation and gene expression changes. Functional analysis indicated that, particularly, transcript 2 (coding for DNMT3A2) activates proliferation and induces loss of a primitive immunophenotype, whereas transcript 4 interferes with colony formation of the erythroid lineage. Notably, in acute myeloid leukemia expression of transcript 2 correlates with its in vitro DNA methylation and gene expression signatures and is associated with overall survival, indicating that DNMT3A variants also affect malignancies. Our results demonstrate that specific DNMT3A variants have a distinct epigenetic and functional impact. Particularly, DNMT3A2 triggers hematopoietic differentiation and the corresponding signatures are reflected in acute myeloid leukemia.

| S-EPMC6293073 | biostudies-literature

Variants of DNMT3A cause transcript-specific DNA methylation and gene expression changes

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-12-10 | GSE103008 | GEO

Biallelic RNU12 noncoding variants cause CDAGS syndrome

Project description:Biallelic RNU12 noncoding variants cause CDAGS syndrome

| PRJNA648415 | ENA

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Project description:Variants of DNMT3A cause transcript-specific DNA methylation changes

| PRJNA399747 | ENA

Homo sapiens

Project description:Variants of DNMT3A cause transcript-specific gene expression changes

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Heterozygous variants in POLR1A cause diverse human phenotypes

Project description:Heterozygous variants in POLR1A cause diverse human phenotypes

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Gain of function DNMT3A mutations cause microcephalic dwarfism and hypermethylation of Polycomb-regulated regions (human Illumina methylation)

Project description:DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, encoding the DNA methyltransferase DNMT3A, that cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2/3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation canyons/valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3aW326R pluripotent cells in vitro, and is also evident in Dnmt3aW326R/+ dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2/3 normally limits DNA methylation of polycomb-marked regions. Our findings implicate the interplay between DNA methylation and polycomb at key developmental regulators as a determinant of organism size in mammals. This series contains Infinium methylation data on human blood and fibroblast samples.

2018-11-26 | GSE120428 | GEO

Systematic profiling of DNMT3A variants reveals protein instability mediated by the DCAF8 E3 ubiquitin ligase adaptor

Project description:Clonal hematopoiesis is a prevalent age-related condition associated with greatly increased risk of hematologic malignancies. Mutations in DNA methyltransferase 3A (DNMT3A) are the most common drivers of this state and contribute to multiple types of hematologic malignancy. DNMT3A variants occur across the gene and some are associated with particular disease states, but the functional relevance and mechanisms of pathogenesis of the majority of the mutations is unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated DNMT3A mutations, finding that 74% were loss-of-function mutations. Nearly half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and AML development. To identify the mechanisms underlying the instability, we conducted a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and therapeutic significance for patients with hematologic disease.

2021-06-24 | GSE178798 | GEO

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