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Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [RNA-seq]

ABSTRACT: The de novo DNA methyltransferase Dnmt3a is mutated in human acute myeloid leukemia, and suppresses tumorigenesis in murine models of leukemia and lung cancer. Conversely, deregulation of the other de novo DNA methyltransferase, Dnmt3b, predominantly promotes tumorigenesis. However, the molecular mechanisms underlying the roles of Dnmt3a and Dnmt3b in cancer remain poorly understood. Using conditional knockout mice, here we show that Dnmt3a -- but not Dnmt3b -- strongly protects epidermal stem cells from carcinogen-induced tumor initiation, without affecting the progression of benign lesions to aggressive carcinomas. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous cell carcinomas acquired a more aggressive fate and even became metastatic, indicating that Dnmt3b is tumor-suppressive, rather than pro-tumorigenic, in epidermal neoplasia. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers, and inhibits the expression of lipid metabolism and cell proliferation genes by directly methylating their promoters. Altogether, we demonstrate that Dnmt3a, but not Dnmt3b, is critical for suppressing epidermal tumor initiation, while both enzymes prevent tumor progression.

OTHER RELATED OMICS DATASETS IN: PRJNA390300PRJNA390301

ORGANISM(S): Mus musculus

PROVIDER: GSE92423 | GEO | 2020/04/07

REPOSITORIES: GEO

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Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [MeDIP-seq]

Project description:The de novo DNA methyltransferase Dnmt3a is mutated in human acute myeloid leukemia, and suppresses tumorigenesis in murine models of leukemia and lung cancer. Conversely, deregulation of the other de novo DNA methyltransferase, Dnmt3b, predominantly promotes tumorigenesis. However, the molecular mechanisms underlying the roles of Dnmt3a and Dnmt3b in cancer remain poorly understood. Using conditional knockout mice, here we show that Dnmt3a -- but not Dnmt3b -- strongly protects epidermal stem cells from carcinogen-induced tumor initiation, without affecting the progression of benign lesions to aggressive carcinomas. Only upon combined deletion of Dnmt3a and Dnmt3b, squamous cell carcinomas acquired a more aggressive fate and even became metastatic, indicating that Dnmt3b is tumor-suppressive, rather than pro-tumorigenic, in epidermal neoplasia. Mechanistically, Dnmt3a promotes the expression of epidermal differentiation genes by interacting with their enhancers, and inhibits the expression of lipid metabolism and cell proliferation genes by directly methylating their promoters. Altogether, we demonstrate that Dnmt3a, but not Dnmt3b, is critical for suppressing epidermal tumor initiation, while both enzymes prevent tumor progression.

2020-03-26 | GSE92422 | GEO

Dnmt3a associates with promoters and enhancers to protect epidermal stem cells from cancer [ChIP-seq]

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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.

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Structure-guided functional suppression of AML-associated DNMT3A R882 mutations [methylation]

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Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation

Project description:DNA methylation is an epigenetic modification associated with transcriptional repression of promoters and is essential for mammalian development. Establishment of DNA methylation is mediated by the de novo DNA methyltransferases DNMT3A and DNMT3B, whereas DNMT1 ensures maintenance of methylation through replication. Absence of these enzymes is lethal, and somatic mutations in these genes have been associated with several human diseases. How genomic DNA methylation patterns are regulated remains poorly understood, as the mechanisms that guide recruitment and activity of DNMTs in vivo are largely unknown. To gain insights into this matter we determined chromosomal binding and site-specific activity of the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B. We show that both enzymes localize to methylated, CpG dense regions in mouse stem cells, yet are excluded from active promoters and enhancers. By specifically measuring sites of de novo methylation, we observe that enzymatic activity reflects chromosomal binding. De novo methylation increases with CpG density, yet is excluded from nucleosomes. Notably, we observed selective binding of DNMT3B to the bodies of transcribed genes, which leads to their preferential methylation. This targeting to transcribed sequences requires SETD2-mediated methylation of lysine 36 on histone H3 and a functional PWWP domain of DNMT3B. Together these findings reveal how sequence and chromatin cues guide de novo methyltransferase activity to ensure methylome integrity. Genome-wide binding analysis for biotin-tagged DNMT3A2 and DNMT3B and variants in wild type ES, wild type neuroprogenitor cells, ES cells triple-KO for Dnmt1,3a,3b and ES cell mutant for Setd2

2015-01-20 | E-GEOD-57412 | biostudies-arrayexpress

Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation

Project description:This SuperSeries is composed of the SubSeries listed below. DNA methylation is an epigenetic modification associated with transcriptional repression of promoters and is essential for mammalian development. Establishment of DNA methylation is mediated by the de novo DNA methyltransferases DNMT3A and DNMT3B, whereas DNMT1 ensures maintenance of methylation through replication. Absence of these enzymes is lethal, and somatic mutations in these genes have been associated with several human diseases. How genomic DNA methylation patterns are regulated remains poorly understood, as the mechanisms that guide recruitment and activity of DNMTs in vivo are largely unknown. To gain insights into this matter we determined chromosomal binding and site-specific activity of the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B. We show that both enzymes localize to methylated, CpG dense regions in mouse stem cells, yet are excluded from active promoters and enhancers. By specifically measuring sites of de novo methylation, we observe that enzymatic activity reflects chromosomal binding. De novo methylation increases with CpG density, yet is excluded from nucleosomes. Notably, we observed selective binding of DNMT3B to the bodies of transcribed genes, which leads to their preferential methylation. This targeting to transcribed sequences requires SETD2-mediated methylation of lysine 36 on histone H3 and a functional PWWP domain of DNMT3B. Together these findings reveal how sequence and chromatin cues guide de novo methyltransferase activity to ensure methylome integrity. Refer to individual Series

2015-01-22 | E-GEOD-57413 | biostudies-arrayexpress

Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation

Project description:DNA methylation is an epigenetic modification associated with transcriptional repression of promoters and is essential for mammalian development. Establishment of DNA methylation is mediated by the de novo DNA methyltransferases DNMT3A and DNMT3B, whereas DNMT1 ensures maintenance of methylation through replication. Absence of these enzymes is lethal, and somatic mutations in these genes have been associated with several human diseases. How genomic DNA methylation patterns are regulated remains poorly understood, as the mechanisms that guide recruitment and activity of DNMTs in vivo are largely unknown. To gain insights into this matter we determined chromosomal binding and site-specific activity of the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B. We show that both enzymes localize to methylated, CpG dense regions in mouse stem cells, yet are excluded from active promoters and enhancers. By specifically measuring sites of de novo methylation, we observe that enzymatic activity reflects chromosomal binding. De novo methylation increases with CpG density, yet is excluded from nucleosomes. Notably, we observed selective binding of DNMT3B to the bodies of transcribed genes, which leads to their preferential methylation. This targeting to transcribed sequences requires SETD2-mediated methylation of lysine 36 on histone H3 and a functional PWWP domain of DNMT3B. Together these findings reveal how sequence and chromatin cues guide de novo methyltransferase activity to ensure methylome integrity. Whole-genome bisulfite sequencing for Dnmt1,3a,3b-triple-KO ES cells expressing DNMT3A2 or DNMT3B1 and for Dnmt1,3a,3b,Setd2-KO ES cells expressing DNMT3B1

2015-01-20 | E-GEOD-57411 | biostudies-arrayexpress

Dnmt3L-dependent regulation of DNA methylation promotes stem cells differentiation toward primitive germinal cells [MeDIP-seq]

Project description:The de novo DNA methyltransferase 3-like (Dnmt3L) is a catalytically inactive DNA methylase that has been previously shown to cooperate with Dnmt3a and Dnmt3b to methylate DNA. Dnmt3L is highly expressed in mouse embryonic stem cells (ESC) but its function in these cells is unknown. We here report that Dnmt3L is required for the differentiation of ESC into primordial germ cells (PGC) through activation of the homeotic gene Rhox5. By genome-wide analysis we found that Dnmt3L is a positive regulator of methylation at gene bodies of housekeeping genes and a negative regulator of methylation at promoters of bivalent genes. We demonstrate that Dnmt3L interacts with the Polycomb PRC2 complex in competition with the DNA methyl transferases Dnmt3a and Dnmt3b to maintain low the methylation level at H3H27me3 regions. Thus in ESC, Dnmt3L counteracts the activity of de novo DNA methylases to keep low the level of DNA methylation at developmental gene promoters. Examination of 5mC in shGFP and shDnmt3L ESC by MeDIP-Seq

2013-09-27 | E-GEOD-44642 | biostudies-arrayexpress

De novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells to a pluripotent state

Project description:Induced pluripotent stem cells (iPSCs) are generated from somatic cells by the transduction of defined transcription factors and involves dynamic changes in DNA methylation. While the reprogramming of somatic cells is accompanied by de-methylation of pluripotency genes, the functional importance of de novo DNA methylation has not been clarified. Here, using loss-of-function studies, we generated iPSCs from fibroblasts that were deficient in de novo DNA methylation mediated by Dnmt3a and Dnmt3b. These iPSCs reactivated pluripotency genes, underwent self-renewal and showed restricted developmental potential which was rescued upon re-introduction of Dnmt3a and Dnmt3b. We conclude that de novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells. RNA levels of Dnmt3ab deficient iPSC cell lines were compared to control iPSC cell lines

2011-05-16 | E-GEOD-28629 | biostudies-arrayexpress

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