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Variants of DNMT3A cause transcript-specific gene expression changes

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103007 | GEO | 2018/12/10

REPOSITORIES: GEO

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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

Effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (ChIP-seq)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided H3K4me1, H3K27ac and H3K79me2 ChIP-seq profiling data showing effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction. ChIP-seq analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) 3 weeks post-transduction. Antibodies of H3K4me1, H3K27ac and H3K79me2 were used.

2016-06-23 | E-GEOD-71472 | biostudies-arrayexpress

Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise.

Project description:Inbred individuals reared in controlled environments display considerable variance in many complex traits. The underlying cause of this variability has been an enigma, hence the term intangible variation. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process. Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28), show greater coefficients of variance in body weight than their wildtype littermates. Inbred mice carrying a mutation in Trim28 develop metabolic syndrome and abnormal behaviour with incomplete penetrance. These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans. Liver gene expression in Trim28MommeD9 heterozygotes compared to wildtype littermates.

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Effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (ChIP-seq)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational ‘hotspot’ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of ‘stemness’ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided H3K4me1, H3K27ac and H3K79me2 ChIP-seq profiling data showing effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction.

2016-06-23 | GSE71472 | GEO

Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation [DNA methylation]

Project description:DNA methyltransferase 3A (DNMT3A) is the most frequently mutated gene in clonal hematopoiesis, indicating that it may be essential for hematopoietic differentiation. We therefore addressed the functional relevance of DNMT3A for hematopoietic differentiation of human induced pluripotent stem cells (iPSCs) by knocking out either exon 2, 19, or 23. Directed differentiation towards mesenchymal stromal cells or hematopoietic progenitor cells (iHPCs) was only slightly reduced in exon 19-/- lines. Notably, exon 19-/- and exon 23-/- lines revealed absence of almost the entire de novo DNA methylation during differentiation. Despite the drastic effects on DNA methylation, there was no significant impact on gene expression of iHPCs. Notably, DNA methylation differences in acute myeloid leukemia with/without DNMT3A are related to iHPCs with/without DNMT3A knockout. Our results demonstrate that de novo DNA methylation during hematopoietic differentiation of iPSCs is almost entirely dependent on DNMT3A, while it has little impact on early cell-fate decisions.

2022-05-31 | GSE180402 | GEO

Hematopoietic differentiation of human iPSC is hardly affected by knockouts in DNMT3A exons despite loss of de novo DNA methylation [RNA-seq]

2022-05-31 | GSE180403 | GEO

Epigenetic perturbations by Arg882-mutated DNMT3A potentiate aberrant stem cell gene expression program and acute leukemia development

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

Effect of DNMT3A R882H mutation or WT expression on global DNA methylation patterns of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (eRRBS)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided enhanced Reduced Representation Bisulfite Sequencing (eRRBS) DNA methylome profiling data showing effect of DNMT3A R882H mutation or WT expression on hematopoietic stem/progenitor cells with NRAS G12D co-transduction. eRRBBs DNA methylome analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) at day 16 post-transduction.

2016-06-23 | E-GEOD-71473 | biostudies-arrayexpress

Effect of DNMT3A R882H mutation or WT on gene expression in hematopoietic stem/progenitor cells with NRAS G12D co-transduction (Microarray)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational â??hotspotâ?? at Arg882 (i.e., DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of â??stemnessâ?? gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided microarray data showing effect of R882H-mutated or WT DNMT3A on gene expression among HSPCs with NRAS G12D co-transduction. Microarray analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) at day 12 or day 16 post-transduction.

2016-06-23 | E-GEOD-71437 | biostudies-arrayexpress

Tissue-Biased Expansion of DNMT3A-Mutant Clones Associated with Conserved Epigenetic Alterations

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

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