Gene expression and DNA methylation of lung tumors in Dnmt3a deficient vs. WT mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE32487 | GEO | 2011/10/26
SECONDARY ACCESSION(S): PRJNA147783
REPOSITORIES: GEO
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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.
2011-10-26 | GSE32484 | 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:This SuperSeries is composed of the following subset Series: GSE32415: Mouse lung tumor tissue: Dnmt3a KO vs. Dnmt3a WT GSE32484: DNA methylation of dnmt3a deficient Kras lung tumors and dnmt3a wt Kras lung tumors Refer to individual Series
2011-10-25 | E-GEOD-32487 | biostudies-arrayexpress
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: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.
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Project description:The deregulation of miR-101 and DNMT3a has been implicated in the pathogenesis of multiple tumor types, but whether and how miR-101 silencing and DNMT3a overexpression contribute to lung tumorigenesis remain elusive. Here we show that miR-101 downregulation associates with DNMT3a overexpression in lung cancer cell lines and patient tissues. Ectopic miR-101 expression remarkably abrogated the DNMT3a 3'-UTR luciferase activity corresponding to the miR-101 binding site and caused an attenuated expression of endogenous DNMT3a, which led to a reduction of global DNA methylation and the re-expression of tumor suppressor CDH1 via its promoter DNA hypomethylation. Functionally, restoration of miR-101 expression suppressed lung cancer cell clonability and migration, which recapitulated the DNMT3a knockdown effects. Interestingly, miR-101 synergized with decitabine to downregulate DNMT3a and to reduce DNA methylation. Importantly, ectopic miR-101 expression was sufficient to trigger in vivo lung tumor regression and the blockage of metastasis. Consistent with these phenotypes, examination of xenograft tumors disclosed an increase of miR-101, a decrease of DNMT3a and the subsequent DNA demethylation. These findings support that the loss or suppression of miR-101 function accelerates lung tumorigenesis through DNMT3a-dependent DNA methylation, and suggest that miR-101-DNMT3a axis may have therapeutic value in treating refractory lung cancer.
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Project description:DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) at cytosines is essential for genome regulation and development. Dysregulation of this process is implicated in various diseases, notably cancer. However, the mechanisms underlying DNMT3 substrate recognition and enzymatic specificity remain elusive. Here we report a 2.65-ångström crystal structure of the DNMT3A-DNMT3L-DNA complex in which two DNMT3A monomers simultaneously attack two cytosine-phosphate-guanine (CpG) dinucleotides, with the target sites separated by 14 base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain, a catalytic loop, and DNMT3A homodimeric interface. Arg836 of the target recognition domain makes crucial contacts with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Haematological cancer-associated somatic mutations of the substrate-binding residues decrease DNMT3A activity, induce CpG hypomethylation, and promote transformation of haematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease.
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Project description:DNA methylation, one of the major epigenetic mechanisms, plays critical roles in regulating gene expression, genomic stability and cell lineage commitment. The establishment and maintenance of DNA methylation in mammals is achieved by two groups of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B, which are responsible for installing DNA methylation patterns during gametogenesis and early embryogenesis, and DNMT1, which is essential for propagating DNA methylation patterns during replication. Both groups of DNMTs are multi-domain proteins, containing a large N-terminal regulatory region in addition to the C-terminal methyltransferase domain. Recent structure-function investigations of the individual domains or large fragments of DNMT1 and DNMT3A have revealed the molecular basis for their substrate recognition and specificity, intramolecular domain-domain interactions, as well as their crosstalk with other epigenetic mechanisms. These studies highlight a multifaceted regulation for both DNMT1 and DNMT3A/3B, which is essential for the precise establishment and maintenance of lineage-specific DNA methylation patterns in cells. This review summarizes current understanding of the structure and mechanism of DNMT1 and DNMT3A-mediated DNA methylation, with emphasis on the functional cooperation between the methyltransferase and regulatory domains.
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Project description:Calorie restriction has long been known to extend lifespans and inhibit carcinogenesis in multiple species by slowing age-related epigenetic changes while the underlying mechanisms remain largely unknown. Herein, we found that starvation activated autophagy to remodel DNA methylation profile by inhibiting DNMT3a expression. Autophagy is impaired in chemoresistance which was associated with differential DNA methylation and could be reversed by DNMT3a inhibition. Autophagy activation decreases the expression of DNMT3a mRNA, accompanied with the downregulation of chemoresistance-related Linc00942. Knockdown of Linc00942 reduces DNMT3a expression and genome-wide DNA methylation while Linc00942 overexpression increased DNMT3a expression and correlated hypermethylation in cancer cells and primary tumor tissues. As a result, inhibition of autophagy increases Linc00942 expression to promote chemoresistance and autophagy activation or hypomethylating agent decitabine restores chemosensitivity by reducing global DNA methylation.
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Project description:We quantified the targets and kinetics of DNA methylation acquisition in mouse embryos, and determined the contribution of the de novo methyltransferases DNMT3A and DNMT3B to this process. We provide single-base maps of cytosine methylation by RRBS from the blastocysts to post-implantation stages and in embryos lacking DNMT3A or DNMT3B activity, and performed RNA-Seq in embryos lacking DNMT3B activity.
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