Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of genes regulated by REST in developing hearts

ABSTRACT: Selective suppression of cardiac gene expression by RE-1 silencing transcription factor (REST) in embryonic stage is essential for cardiogenesis and function; however, the underlying mechanism remains unclear. In this study, we show that REST suppression of cardiac genes during development is temporarily regulated through non-CpG methylation at REST binding sites. Gene expression analyses revealed that the expression of Hcn2 (hyperpolarization-activated cyclic nucleotide-gated ion channel 2), a REST-targeted gene, was developmentally upregulated, while DNMT3B level and REST expression was downregulated. Concurrently, bisulﬁte sequencing and chromatin immunoprecipitation (ChIP) analyses showed that non-CpG methylation of the REST site located in the Hcn2 intron 1 and its co-occupancy by REST and DNMT3B were diminished at E?. Further in vitro inhibition and in vivo myocardial deletion of Rest and Dnmt3b uncovered that non-CpG methylation of the REST site by DNMT3B promoted REST binding to suppress Hcn2 transcription in the embryonic stage. Moreover, using an integrated approach of transcriptomic analysis, ChIP assay, and bisulfate sequencing, we showed that the same mechanism regulated the expression of ~30% REST targeted genes. The expression of these genes was developmentally upregulated as Hcn2. Together, our results suggest that non-CpG methylation at a subset of transcription factor binding sites may regulate cardiac gene program critical for heart development and its dysregulation may contribute to heart disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE80378 | GEO | 2017/02/13

SECONDARY ACCESSION(S): PRJNA318773

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

DNA methylation in the colon of Dnmt3b-induced and control mice

Project description:The methylation status of colon epithelial cells was profiled in wild type mice and mice expressing a Dnmt3b transgene. Genome-scale methylation profiles were generated using reduced representation bisulfite sequencing (RRBS), with CpG methylation scored by promoter and also summarized by gene. Dnmt3b expression is associated with a strong increase in de novo methylation of a discrete subset of "methylation sensitive" genes which show a strong concordance with genes methylated in human colon cancer. These results, together with further analysis, indicate that colon epithelial cell methylation in the Dnmt3b mouse model predicts DNA methylation of human colon cancer with high confidence. Three each of Dnmt3b-induced and control mice, each split into two fractions.

2011-10-25 | E-GEOD-26758 | biostudies-arrayexpress

DNA methylation in the colon of Dnmt3b-induced and control mice

2011-10-26 | GSE26758 | GEO

DNMT3B7 disrupts embryonic development and accelerates lymphomagenesis

Project description:Cancer cells have an altered distribution of DNA methylation and express aberrant DNA methyltransferase 3B transcripts, which encode truncated proteins. To test if a truncated DNMT3B isoform disrupts DNA methylation in vivo, we constructed transgenic mice expressing DNMT3B7, a common truncated DNMT3B isoform in cancer cells. DNMT3B7 transgenic mice exhibit altered embryonic development, including lymphopenia, craniofacial abnormalities, and cardiac defects, similar to Dnmt3b-deficient animals, but rarely develop cancer. However, DNMT3B7 expression increases the frequency of mediastinal lymphomas in Eμ−myc animals. Eμ-myc/DNMT3B7 lymphomas have more chromosomal rearrangements, increased global methylation levels, and more locus-specific perturbations in DNA methylation patterns compared to Eμ-myc lymphomas. Our results demonstrate that a truncated DNMT3B protein can alter tumorigenesis, suggesting a similar role in human tumors. Direct comparison of DNA methylation in lymphoma samples from Eu-Myc vs Eu-Myc/Dnmt3b7 mice.

2010-07-30 | E-GEOD-21273 | biostudies-arrayexpress

Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [gene expression]

Project description:Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depltion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in unprecedented detail. DNMT3B occupancy regulates methylation during differentiation, while an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated nonCpG methylation, while DNMT3L influenced the activity of DNMT3B toward nonCpG versus CpG site methylation. Taken together, these data reveal new functional targets of each DNMT suggesting that isoform selective inhibition would be therapeutically advantageous. Affymetrix gene expression Human Gene 1.0 ST microarray of NCCIT human embryonic carcinoma cells (13 samples in duplicate).

2014-10-20 | E-GEOD-54841 | biostudies-arrayexpress

Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms

Project description:Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterizations of DNMT3A and DNMT3B, here we uncovered distinct and interrelated modes-of-action underlying their CpG site and flanking sequence interaction. Strikingly, K777 of DNMT3B makes direct contacts with the DNA base at the +1 flank position of the cytosine methylation site, which contrasts with its counterpart in DNMT3A that forms base-specific contacts with the CpG site. Consequently, there is a divergent substrate and flanking sequence preference between DNMT3A and DNMT3B in vitro and in cells, thus providing an explanation for site-specific epigenomic alterations seen in ICF syndrome patients with DNMT3B mutations. Together, this study reveals crucial, yet complicated interplays of DNMT3s, DNA sequences and resultant methylation.

2020-06-18 | GSE145899 | GEO

Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome [MBD-seq]

Project description:Global patterns of DNA methylation, mediated by the DNA methyltransferases (DNMTs), are disrupted in all cancers by mechanisms that remain largely unknown, hampering their development as therapeutic targets. Combinatorial acute depltion of all DNMTs in a pluripotent human tumor cell line, followed by epigenome and transcriptome analysis, revealed DNMT functions in unprecedented detail. DNMT3B occupancy regulates methylation during differentiation, while an unexpected interplay was discovered in which DNMT1 and DNMT3B antithetically regulate methylation and hydroxymethylation in gene bodies, a finding confirmed in other cell types. DNMT3B mediated nonCpG methylation, while DNMT3L influenced the activity of DNMT3B toward nonCpG versus CpG site methylation. Taken together, these data reveal new functional targets of each DNMT suggesting that isoform selective inhibition would be therapeutically advantageous. NCCIT cells were transfected with siRNAs against DNMT3B and a no-target control. Genomic DNA was extracted, and subsequently applied to affinity MBD-bound magnetic beads (Ribomed) to enrich methylated DNA sequences.

2014-10-20 | E-GEOD-54842 | biostudies-arrayexpress

Flanking sequence preference modulates de novo DNA methylation in the mouse genome

Project description:Mammalian de novo DNA methyltransferases (DNMT) are responsible for the establishment of cell-type-specific DNA methylation in healthy and diseased tissues. Through genome-wide analysis of de novo methylation activity in murine stem cells we uncover that DNMT3A prefers to methylate CpGs followed by cytosines or thymines, while DNMT3B predominantly methylates CpGs followed by guanines or adenines. These signatures are further observed at non-CpG sites, resembling methylation context observed in specialised cell types, including neurons and oocytes. We further show that these preferences result from structural differences in the catalytic domains of the two de novo DNMTs and are not a consequence of differential recruitment to the genome. Molecular dynamics simulations suggest that, in case of human DNMT3A, the preference is due to favourable polar interactions between the flexible Arg836 side chain and the guanine that base-pairs with the cytosine following the CpG. By exchanging arginine to a lysine, the corresponding sidechain in DNMT3B, the sequence preference is reversed, confirming the requirement for arginine at this position. This context-dependent de novo DNA methylation by DNMT3A and DNMT3B, provides additional insights into the complex regulation of methylation patterns.

2020-11-16 | GSE151992 | GEO

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

DNMT3B7 disrupts embryonic development and accelerates lymphomagenesis

2010-07-30 | GSE21273 | GEO

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data