RNautophagic regulation of DNMT3a-dependent DNA methylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA874430 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21283840_1.fastq.gz | Fastqsanger.gz | |||
| SRR21283840_2.fastq.gz | Fastqsanger.gz | |||
| SRR21283841_1.fastq.gz | Fastqsanger.gz | |||
| SRR21283841_2.fastq.gz | Fastqsanger.gz | |||
| SRR21283842_1.fastq.gz | Fastqsanger.gz |
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Project description:RNautophagic regulation of DNMT3a-dependent DNA methylation
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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.
2023-08-08 | GSE210596 | GEO
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. Taken together, our study identifies a novel methylation cascade linking impaired RNautophagy to global hypermethylation in chemoresistance, and provides a rationale for repurposing decitabine to overcome chemoresistance in cancer treatment.
2023-09-12 | GSE212184 | GEO
Project description:DNA methylation is a central epigenetic modification that has essential roles in cellular processes including chromatin structure, gene regulation, development and disease. The de novo DNA methyltransferases are responsible for the generation of genomic methylation patterns, but the underlying mechanisms are still poorly understood. Here, we show that phosphorylation of DNMT3A by the CK2 protein kinase regulates the establishment of DNA methylation patterns. We find that DNMT3A is phosphorylated by CK2 at two key residues located near its PWWP domain. We observed that, through phosphorylation of these residues, CK2 negatively regulates DNMT3AM-bM-^@M-^Ys ability to methylate DNA and consistent with this, CK2 was found to decrease overall genomic level of 5-methylcytosine. Further, genome-wide DNA methylation analysis in CK2-depleted cells revealed that CK2 affects primarily CpG methylation of several heterochromatin repeats as well as Alu elements. Along these lines, we found that CK2-mediated phosphorylation of DNMT3A was required for its proper heterochromatin localization. Our results define phosphorylation as a new mode of regulation of de novo DNA methyltransferase function. These findings further uncover a previously unrecognized mechanism for the regulation of methylation at repetitive elements. They shed new light into the origin of DNA methylation patterns. Bisulphite converted DNA from 6 samples were hybridised to the Illumina Infinium 27K Human Methylation Beadchip v1.2
2014-07-17 | E-GEOD-26164 | biostudies-arrayexpress
Project description:DNA methylation is a central epigenetic modification that has essential roles in cellular processes including chromatin structure, gene regulation, development and disease. The de novo DNA methyltransferases are responsible for the generation of genomic methylation patterns, but the underlying mechanisms are still poorly understood. Here, we show that phosphorylation of DNMT3A by the CK2 protein kinase regulates the establishment of DNA methylation patterns. We find that DNMT3A is phosphorylated by CK2 at two key residues located near its PWWP domain. We observed that, through phosphorylation of these residues, CK2 negatively regulates DNMT3A’s ability to methylate DNA and consistent with this, CK2 was found to decrease overall genomic level of 5-methylcytosine. Further, genome-wide DNA methylation analysis in CK2-depleted cells revealed that CK2 affects primarily CpG methylation of several heterochromatin repeats as well as Alu elements. Along these lines, we found that CK2-mediated phosphorylation of DNMT3A was required for its proper heterochromatin localization. Our results define phosphorylation as a new mode of regulation of de novo DNA methyltransferase function. These findings further uncover a previously unrecognized mechanism for the regulation of methylation at repetitive elements. They shed new light into the origin of DNA methylation patterns.
2014-07-17 | GSE26164 | GEO
Project description:DNA methylation is a central epigenetic modification that has essential roles in cellular processes including chromatin structure, gene regulation, development and disease. The de novo DNA methyltransferases are responsible for the generation of genomic methylation patterns, but the underlying mechanisms are still poorly understood. Here, we show that phosphorylation of DNMT3A by the CK2 protein kinase regulates the establishment of DNA methylation patterns. We find that DNMT3A is phosphorylated by CK2 at two key residues located near its PWWP domain. We observed that, through phosphorylation of these residues, CK2 negatively regulates DNMT3A’s ability to methylate DNA and consistent with this, CK2 was found to decrease overall genomic level of 5-methylcytosine. Further, genome-wide DNA methylation analysis in CK2-depleted cells revealed that CK2 affects primarily CpG methylation of several heterochromatin repeats as well as Alu elements. Along these lines, we found that CK2-mediated phosphorylation of DNMT3A was required for its proper heterochromatin localization. Our results define phosphorylation as a new mode of regulation of de novo DNA methyltransferase function. These findings further uncover a previously unrecognized mechanism for the regulation of methylation at repetitive elements. They shed new light into the origin of DNA methylation patterns.
2014-07-17 | GSE26810 | GEO
Project description:Dnmt3a is the most recurrently mutated gene in clonal hematopoiesis (CH) and it is a critical regulator of hematopoietic stem cells (HSCs). Conditional deletion of Dnmt3a in mouse HSC results in enhanced self-renewal but impaired differnetiation. Dnmt3a encodes for a de novo DNA methyltransferase enzyme but both mouse and human cells with loss of Dnmt3a show minimal change in DNA methylation levels which do not correlate with gene expression differences. To understand if these changes are due to non-canonical function of Dnmt3a, we generated varying levels of DNA methyaltion-impared Dnmt3a mouse models. Our data depicts that DNA methyaltion-impaired Dnmt3a phenocopy wild-type in serial transplant. And Dnmt3a methyltransferase-deficient HSCs showed differntially methylated regions (DMRs) and gene expression pattern that overlapped with Dnmt3a-null HScs. Suggesting that Dnmt3a has important non-canonical function that partially regulates HSC fate. Dnmt3a-null HSC increased HSC self-renwal and can be transplanted indefinitely and increase longevity with no erosion of telomere length. Dnmt3a-null HSCs showed increased telomere at baseline and maintained overa serial transplant and increased telomerase activity. The role of Dnmt3a in telomere maintenance was not strictly linked to elongated telomere length but in regulation of DNA damage response that occurs at stressed telomeres. These data show a unidentified role of Dnmt3a in HSC telomere maintenance that is note related to DNA methylation function.
2024-09-10 | GSE272913 | GEO
Project description:DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) 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-Å crystal structure of the DNMT3A-DNMT3L-DNA complex where two DNMT3A monomers simultaneously attack two CpG dinucleotides, with the target sites separated by fourteen base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain (TRD), a catalytic loop and DNMT3A homodimeric interface. A TRD residue Arg836 makes crucial contact with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Hematological cancer-associated somatic mutations at the substrate-binding sites decrease DNMT3A activity, induce CpG hypomethylation and promote transformation of hematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its etiologic link to human disease.
2018-01-01 | GSE99391 | GEO
Project description:DNA methylation by de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) 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-Å crystal structure of the DNMT3A-DNMT3L-DNA complex where two DNMT3A monomers simultaneously attack two CpG dinucleotides, with the target sites separated by fourteen base pairs within the same DNA duplex. The DNMT3A-DNA interaction involves a target recognition domain (TRD), a catalytic loop and DNMT3A homodimeric interface. A TRD residue Arg836 makes crucial contact with CpG, ensuring DNMT3A enzymatic preference towards CpG sites in cells. Hematological cancer-associated somatic mutations at the substrate-binding sites decrease DNMT3A activity, induce CpG hypomethylation and promote transformation of hematopoietic cells. Together, our study reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its etiologic link to human disease.
2018-01-01 | GSE99390 | GEO
Project description:Establishment of the DNA methylation landscape of mammalian oocytes, mediated by the DNMT3A-DNMT3L complex, is crucial for reproduction and development. In mouse oocytes, high levels of DNA methylation occur exclusively in the transcriptionally active regions, with moderate to low levels of methylation in other regions. Histone H3K36me3 mediates the high levels of methylation in the transcribed regions; however, it is unknown which histone mark guides the methylation in the other regions. Here, we show that, in mouse oocytes, H3K36me2 is highly enriched in the X chromosome and is broadly distributed across all autosomes. Upon H3K36me2 depletion, DNA methylation in moderately methylated regions is selectively affected, and a methylation pattern unique to the X chromosome is switched to an autosome-like pattern. Furthermore, we find that simultaneous depletion of H3K36me2 and H3K36me3 results in global hypomethylation, comparable to that of DNMT3A depletion. Therefore, the two histone marks jointly provide the chromatin platform essential for guiding DNMT3A-dependent DNA methylation in mouse oocytes.
2022-07-07 | GSE183969 | GEO