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| Status |
Public on Nov 14, 2025 |
| Title |
Disordered DNA methylation leads to targetable transcriptional plasticity in ATRT [WGBS] |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by high throughput sequencing
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| Summary |
Atypical teratoid rhabdoid tumor (ATRT) is a highly aggressive but genetically simple pediatric central nervous system tumor, defined by biallelic inactivation of the chromatin regulator SMARCB1 with remarkably few other cooperating mutations. Despite its genetic homogeneity, ATRT exhibits profound clinical and epigenetic heterogeneity, with three major subgroups (ATRT-TYR, ATRT-MYC, and ATRT-SHH) defined by DNA methylation and transcriptional signatures. Beyond these subgroup-defining features, we aimed to investigate epigenetic variability within tumors by applying whole-genome bisulfite sequencing and probabilistic modeling to quantify stochastic DNA methylation in primary ATRT samples encompassing all three subgroups. We show that ATRT exhibits a destabilized and increasingly stochastic methylome. While ATRT global methylation patterns diverge according to subgroup, some methylation perturbations, such as hypermethylation and increased methylation entropy over bivalent promoters, are consistent across subgroups. We find that methylation stochasticity alterations map onto potential drivers of ATRT, such as LIN28a, the HOXD cluster for ATRT-MYC, and OTX2 for ATRT-TYR, and identify actionable targets, such as hypermethylation of the tumor suppressor CDKN2a across all subgroups. We investigate the sensitivity of the aberrant DNA methylation landscape of ATRT to pharmacologic DNA methyltransferase inhibition and histone deacetylase inhibition (HDACi). We show that decitabine leads to profound demethylation of patient-derived ATRT cell lines, including reversal of hypermethylation at bivalent promoters and the CDKN2a locus. The addition of HDACi leads to dramatic gene expression changes, including upregulation of innate immune signaling pathways, such as STING/interferon signaling, genes under the regulation of bivalent promoters, and reactivation of the tumor suppressor CDKN2A. The combination of DNMTi and HDACi synergistically reduces cell viability. Taken together, we show that ATRT has a highly stochastic methylome sensitive to epigenetic manipulation.
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| Overall design |
WGBS on 22 primary patient samples of ATRT and 4 normal fetal brain controls. Additional files include WGBS output from 4 ATRT cell lines, CHLA02, CHLA05, CHLA06, and CHLA266, treated with 5 days of 100 nM decitabine +/- RG2833.
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Raw files for human/patient samples were not submitted to GEO due to concerns about submitting personally identifiable sequence data for open access.
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| Contributor(s) |
Koldobskiy M, Tetens A |
| Citation missing |
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| Submission date |
Jul 01, 2025 |
| Last update date |
Nov 15, 2025 |
| Contact name |
Michael Koldobskiy |
| E-mail(s) |
mak@jhmi.edu
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| Organization name |
Johns Hopkins University
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| Department |
Oncology
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| Street address |
1800 Orleans St., Bloomberg 11379
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| City |
Baltimore |
| State/province |
MD |
| ZIP/Postal code |
21205 |
| Country |
USA |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (26)
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| Relations |
| BioProject |
PRJNA1284951 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE301412_RAW.tar |
13.6 Gb |
(http)(custom) |
TAR (of BW) |
| Raw data not provided for this record |
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