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Series GSE129136 Query DataSets for GSE129136
Status Public on May 13, 2019
Title Pervasive H3K27 acetylation leads to ERV expression and a therapeutic vulnerability in H3K27M gliomas [ChIP-Seq 2]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Epigenetic alterations are recurrently observed in cancer and are the subject of active therapeutic investigations. Midline high-grade gliomas (HGGs) are deadly brain tumors characterized by lysine-to-methionine substitutions at position 27 in histone 3 (H3) variants (denoted H3K27M), which are core components of the nucleosome. H3K27M, the first event in midline HGG development, results in a drastic loss of the repressive histone mark H3K27 tri-methylation (H3K27me3), and a notable increase in H3K27 acetylation (H3K27ac), a mark associated with active chromatin and cellular identity. H3K27ac gain was suggested to promote tumorigenesis in H3K27M-HGGs, but how these opposing marks shape oncogenesis remains controversial. We therefore characterized the active regulatory chromatin states in H3.3K27M and H3K27 wild-type HGGs and in H3.3K27M CRISPR/Cas9 knockout tumor-derived cell lines, as an isogenic tumor model of the mutation. We show that H3.3K27M-HGGs have distinct promoter, enhancer, super-enhancer, and core transcription factor circuitries from wild-type HGGs. However, while removal of H3.3K27M restores gross H3K27ac levels to those of wild-type HGGs, we observe minimal disruption of H3K27ac deposition at these active transcriptional elements, suggesting that they are a function of the cell of origin and independent of direct H3K27M mutagenesis and active regulation. Using quantitative ChIP-seq, we show that in H3.3K27M-HGGs, H3K27ac is pervasively deposited across the genome, including at normally silent repeat elements, leading to their increased baseline expression. H3.3K27M cells respond to DNA demethylating agents and histone deacetylase inhibitors, which further increase repeat element expression, including that of specific endogenous retroviral (ERVs) families. Our findings decouple cell lineage programs from H3K27M-dependent pervasive deposition of H3K27 acetylation. De-repression of ERVs may enhance the triggering of innate immune pathways, representing a therapeutic vulnerability in H3.3K27M HGGs.
Overall design We sequenced 3 H3.3K27WT and 2 H3.3K27M human HGG tumors by H3K27ac ChIP-seq. Additionally, we sequenced unedited (2 replicates) and Crispr/Cas9 H3.3K27M-KO clones (4 replicates) for two cell lines (DIPGXIII and BT245).
Contributor(s) Krug B, De Jay N, Harutyunyan AS, Deshmukh S, Marchione DM, Guilhamon P, Bertrand KC, Mikael LG, McConechy MK, Chen CC, Khazaei S, Koncar RF, Agnihotri S, Faury D, Ellezam B, Weil AG, Ursini-Siegel J, De Carvalho DD, Dirks PB, Lewis PW, Salomoni P, Lupien M, Arrowsmith C, Lasko PF, Majewski J, Garcia BA, Kleinman CL, Jabado N, Mack SC
Citation(s) 31085178, 33207202
Submission date Apr 01, 2019
Last update date Dec 08, 2020
Contact name Nada Jabado
Organization name McGill University
Department Department of Pediatrics
Lab Jabado Lab
Street address 1001 Décarie Boulevard
City Montreal
State/province Québec
ZIP/Postal code H4A 3J1
Country Canada
Platforms (4)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (22)
GSM3701126 BT245-KO-C4P6_H3K27ac
GSM3701127 BT245-KO-C2P3_H3K27ac
GSM3701128 BT245-NKO-C1P5_H3K27ac
This SubSeries is part of SuperSeries:
GSE128745 Pervasive H3K27 acetylation leads to ERV expression and a therapeutic vulnerability in H3K27M gliomas
BioProject PRJNA530222
SRA SRP190030

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Supplementary file Size Download File type/resource
GSE129136_raw_counts_Repbase.txt.gz 20.7 Kb (ftp)(http) TXT
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