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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Aug 30, 2019 |
| Title |
H3K36me2 recruits DNMT3A and shapes intergenic DNA methylation landscapes |
| Organisms |
Drosophila melanogaster; Homo sapiens; Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Expression profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
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| Summary |
Enzymes catalyzing CpG methylation in DNA, including DNMT1 and DNMT3A/B, are indispensable for mammalian tissue development and homeostasis. They are also implicated in human developmental disorders and cancers, supporting a critical role of DNA methylation during cell fate specification and maintenance. Recent studies suggest that histone post-translational modifications (PTMs) are involved in specifying patterns of DNMT localization and DNA methylation at promoters and actively transcribed gene bodies. However, mechanisms governing the establishment and maintenance of intergenic DNA methylation remain poorly understood. Germline mutations in DNMT3A lead to a childhood overgrowth syndrome that is phenotypically overlapping with Sotos syndrome caused by haploinsufficiency of NSD1, a histone methyltransferase catalyzing di-methylation on H3K36 (H3K36me2), pointing to a potential mechanistic link between the two disorders. Here we report that NSD1-mediated H3K36me2 is required for recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows binding and activity of DNMT3A are co-localized with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of NSD1 and its paralogue NSD2 in mouse and human cells redistributes DNMT3A to H3K36me3-marked gene bodies and reduces intergenic DNA methylation. NSD1 mutant tumors and Sotos patient samples are also associated with intergenic DNA hypomethylation. Consistently, PWWP-domain of DNMT3A shows dual recognition of H3K36me2/3 in vitro with a higher binding affinity towards H3K36me2, which is abrogated by overgrowth syndrome-derived missense mutations. Taken together, our study uncovers a trans-chromatin regulatory pathway that, when perturbed, promotes neoplastic and developmental overgrowth.
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| Overall design |
WGBS, RNA-seq, and ChIP-seq for DNMT proteins and histone H3 post-translational modifications in C3H10T1/2 cells. WGBS and ChIP-seq for H3K36me2 in human head and neck squamous cell carcinoma cell lines and mouse embryonic stem cells.
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| Contributor(s) |
Weinberg DN, Papillon-Cavanagh S, Chen H, Chen X, Rajagopalan K, Horth C, Yue Y, Nikbakht H, Marchione DM, Harutyunyan A, Jabado N, Garcia BA, Li H, Allis CD, Majewski J, Lu C |
| Citation(s) |
31485078, 35245449 |
| Submission date |
Aug 20, 2018 |
| Last update date |
Mar 15, 2022 |
| Contact name |
Jacek Majewski |
| E-mail(s) |
jacek.majewski@mcgill.ca
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| Organization name |
McGill University
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| Department |
Human Genetics
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| Street address |
740 Dr. Penfield
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| City |
Montreal |
| State/province |
Quebec |
| ZIP/Postal code |
QC H3A 1A4 |
| Country |
Canada |
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| Platforms (8)
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| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL20795 |
HiSeq X Ten (Homo sapiens) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
| GPL21227 |
Illumina HiSeq 2500 (Drosophila melanogaster; Mus musculus) |
| GPL21273 |
HiSeq X Ten (Mus musculus) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL25475 |
Illumina HiSeq 4000 (Drosophila melanogaster; Mus musculus) |
| GPL25476 |
Illumina HiSeq 4000 (Drosophila melanogaster; Homo sapiens) |
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| Samples (43)
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| Relations |
| BioProject |
PRJNA486798 |
| SRA |
SRP158409 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE118785_RAW.tar |
13.5 Gb |
(http)(custom) |
TAR (of BW, TDF) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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