DNMT3A epigenetically regulates key microRNAs involved in epithelial-to-mesenchymal transition in prostate cancer
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ABSTRACT:
PROVIDER: PRJEB41664 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR4903892.fastq.gz | Fastqsanger.gz | |||
| ERR4903893.fastq.gz | Fastqsanger.gz | |||
| ERR4903894.fastq.gz | Fastqsanger.gz | |||
| ERR4903895.fastq.gz | Fastqsanger.gz | |||
| ERR4903896.fastq.gz | Fastqsanger.gz |
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Project description:Epithelial-to-Mesenchymal Transition (EMT) is involved in prostate cancer metastatic progression and its plasticity suggests epigenetic implications. Deregulation of UHRF1/DNMT1, DNMT3A and miRNAs play a role in EMT, but their interplay has not been clarified yet. Here, we identify miR-720 and miR-1260a as new DNMT3A regulators through miRNA microarray performed on UHRF1 silenced Androgen Receptor (AR) non-responsive (PC3) cell extracts, and subsequent target validation and functional overexpression and downregulation in PC3 and AR responsive LNCaP cells, respectively. These miRNAs inversely correlated with DNMT3A in our ex-vivo model of EMT in PC3 but not in LNCaP cells, induced with conditioned media from patient-derived Cancer-Associated Fibroblasts (CM-CAF). miR-720 and miR-1260a were expressed in very few patients from the PRAD TCGA data set expressing an EMT or MET (Mesenchymal-to-Epitelial Transition) signature; miR-200 family (miR-200a/b, -141, -429), along with miR-205 and miR-203, were downregulated in EMT patients as they modulate key EMT factors. These latter miRNAs resulted hyper-methylated at their promoters in our ex-vivo EMT prostate cancer model, while in the EMT PRAD TCGA data set only miR200c and miR141 promoters displayed a diffused hyper-methylated pattern inversely correlated with their transcriptional expression. Chromatin immunoprecipitation experiments performed on CM-CAF induced PC3 cells extracts showed that DNMT3A gets recruited onto the promoters of the latter two miRNAs, coupled with a marked increase of H3K27me3 and H3K9me3 and/or the decrease of H3K4me3 and H3K36me3. Altogether, our results point to a DNMT3A regulatory role of key miRNAs for EMT in prostate cancer.
2021-11-20 | E-MTAB-9835 | biostudies-arrayexpress
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: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:DNA methyltransferase 3A (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns. However, the mechanisms underlying DNMT3A recruitment to and function within different chromatin environments remain unclear. Using a combination of biochemical and structural approaches we find that DNMT3A interacts using multiple interfaces with chromatin; directly binding generic nucleosome features as well as site-specific post-translational histone modifications. The N-terminal region, unique to the DNMT3A1 isoform, is essential for these interactions and stabilises H3K36me2-nucleosome recruitment. Intriguingly, in the same region critical for nucleosome binding we also map a ubiquitylation-dependent recruitment motif (UDR). The UDR binds specifically to ubiquitylated H2AK119, explaining the previously observed recruitment to Polycomb-occupied heterochromatin. A cryo-EM structure of DNMT3A1-DNMT3L with a modified nucleosome reveals that the UDR interacts with the nucleosome surface including the acidic patch. Previously unexplained disease-associated mutations are present in the UDR and ablate nucleosome interactions. This leads to an increased understanding of how DNMT3A1 recruitment occurs in the genome and highlights the importance of multivalent binding of DNMT3A to histone modifications and the nucleosome.
2024-10-16 | PXD056554 | Pride
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.
2011-10-26 | GSE32415 | GEO
Project description:To examine whether Dnmt3a deficiency resulted in genomic methylation changes we performed an unbiased methylome analysis. Methylated DNA isolated from three Dnmt3a deficient and two WT tumors was immunoprecipitated and subjected to high throughput sequencing (MeDIP-Seq). We observed that genes that were less expressed in Dnmt3a deficient tumors tended to have lower methylation levels in gene bodies. Examination of methylcytosine in two tumor types
2011-10-25 | E-GEOD-32484 | biostudies-arrayexpress
Project description:DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By utilizing mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2'-deoxycytidine, as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation.
2017-02-07 | GSE91036 | GEO
Project description:Characterization of epigenetically silenced microRNAs in liver cancer cells
| PRJNA508302 | ENA
Project description:Purpose: Epigenetic regulation contributes to pathogenesis of neurondegenerative disease. We found that dis-regulation of a 242-gene subnetwork related to DNA methylation regulated neuronal differentiation are common in AD and HD. There are two DNA methyltransferases, DNMT1 and DNMT3A, in the subnetwork. DNMT1 is one of top hub genes in the network and likely to play a key regulatory role in the subnetwork. To validate that DNMT1 is a key regulator for the subnetwork, and DNMT3A not as one, we constructed two brain-specific conditional knockout mice. Methods: Cortices were dissected from Dnmt1 conditional knockout (CKO), Dnmt3a CKO, and respective littermate control mice at 18 weeks. RNA was isolated from three biological replicates for each genotype using TRIzol (Invitrogen) extraction and isopropanol precipitation. RNA samples were resuspended in water and further purified with RNeasy columns with on-column DNase treatment (Qiagen). RNA purity was assessed by measuring the A260/A280 ratio using a NanoDrop and RNA quality checked using an Agilent 2100 Bioanalyzer (Agilent Technologies). Approximately 250 ng of total RNA per sample were used for library construction by the TruSeq RNA Sample Prep Kit (Illumina) and sequenced using the Illumina HiSeq 2500 instrument according to the manufacturer's instructions. Sequence reads were aligned to mouse genome assembly mm10 and quantified using Cufflinks. Results: Genes differentially expressed in CKO mice compared to littermate control mice, or the Dnmt1 CKO signature, including GSN (the genes with the largest number of connection in the subnetwork) and SOX10 (a key transcription factor of myelination), significantly overlaps with the subnetwork. Broadly, the Dnmt1 CKO signature is enriched for genes involved in GO biological processes immune response, lipid metabolism, endocytosis, glial cell differentiation, and nerve ensheatment, consistent with biological function of the subnetwork. Moreover, the Dnmt1 CKO mice show increased predilection to seizures, an incidence also increased in patients with AD (Amatniek et al, 2006) as well as juvenile form of HD (Cloud et al, 2012). In contrast, the Dnmt3a CKO signature does not overlap with the subnetwork (p=0.07) and is not enriched for any GO biological process. Conclusions: These results suggest the Dnmt1 regulates common genes related with AD and HD while Dnmt3a has little effect. All of the mice used in this study were handled in accordance with IACUC-approved protocols. Dnmt1flox/flox (Fan et al, 2001; Jackson-Grusby et al, 2001) and Dnmt3aflox/flox (Nguyen et al, 2007) mice were backcrossed onto a C57BL/6 background and crossed with Olig1-cre mice to generate Dnmt1 conditional knockout (Olig1cre/+;Dnmt1flox/flox) and littermate control (Olig1+/+;Dnmt1flox/flox) mice, and Dnmt3a conditional knockout (Olig1cre/+;Dnmt3aflox/flox) and littermate control (Olig1+/+;Dnmt3aflox/flox) mice.
2014-07-31 | E-GEOD-58261 | biostudies-arrayexpress
Project description:Despite the impact of DNMT3A mutation in acute myeloid leukemia has been emphasized, the precise molecular mechanisms in leukemogenesis are largely unknown. Here we show that, in murine transplantation experiments, recipients transplanted with DNMT3A mutant-transduced cells exhibit aberrant hematopoietic stem cell (HSC) accumulation. Differentiation-associated genes are down-regulated without accompanying changes in methylation status of their promoter-associated CpG islands in DNMT3A mutant-transduced stem/progenitor cells. DNMT3A mutant also promotes monoblastic transformation in vitro in combination with HOXA9. Molecularly, DNMT3A mutant interacts with polycomb repressive complex 1 (PRC1), leading to transcriptional silencing of PU.1. Suppression of PRC1 impairs aberrant HSC accumulation and monoblastic transformation. Taken together, our results highlight the functional role of DNMT3A mutation, forming the basis for leukemia development. GFP-labeled empty vector, DNMT3A wild-type (WT), R882H-transduced LSK cells derived from transplanted mice were utilized for compared the expression profiles (3 sorted empty vector-transduced LSK cells, 3 sorted DNMT3A WT-transduced LSK cells, and 3 sorted DNMT3A R882H-transduced LSK cells. Total RNA was extracted by TaKaRa NucleoSpin RNA XS according to the manufacturerâs protocol. Amplification and biotin labeling of fragmented cDNA was carried out from 3.67 ng of total RNA by using NuGen Ovation Pico WTA System V2 (NuGEN) and SureTag Complete DNA Labeling Kit (Agilent). Each 2 μg of cDNA were hybridized to the Agilent SurePrint G3 Mouse Gene Expression 8x60K (Agilent) using Gene Expression Hybridization Kit (Agilent). After scanning, the signal intensity for each feature was measured by Agilent Feature Extraction (Agilent).
2016-02-10 | E-GEOD-55262 | biostudies-arrayexpress