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Series GSE264722 Query DataSets for GSE264722
Status Public on Apr 28, 2024
Title Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity [RRBS]
Organism Homo sapiens
Experiment type Methylation profiling by high throughput sequencing
Summary Isocitrate Dehydrogenase 1 (IDH1) is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of IDH1-mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores anti-tumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show striking, selective hypermethylation and silencing of the cytoplasmic dsDNA sensor, CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase activates cGAS, triggering viral mimicry and stimulating anti-tumor immunity. Thus, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous reverse transcriptase activity to the mechanism of action of an FDA-approved oncology drug.
 
Overall design We used reduced-representation bisulfite sequencing (RRBS) of a set of human ICC cell lines to investigate DNA methylation status on the promoter region of interested genes in mIDH1 model tested (N=3 cell lines), as compared with all IDH1 WT models (N=12 cell lines)
 
Contributor(s) Sussman J, Wu MJ, Kammula AV, Manguso RT, Bardeesy N
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Submission date Apr 23, 2024
Last update date Apr 30, 2024
Contact name Robert Manguso
E-mail(s) rmanguso@broadinstitute.org
Organization name Broad Institute of MIT and Harvard
Street address 75 Ames Street
City Cambridge
State/province MA
ZIP/Postal code 02142
Country USA
 
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (15)
GSM8226604 RRBS, HuH28 in vitro
GSM8226605 RRBS, SG231 in vitro
GSM8226606 RRBS, SNU308 in vitro
This SubSeries is part of SuperSeries:
GSE264730 Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity
Relations
BioProject PRJNA1103856

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Supplementary file Size Download File type/resource
GSE264722_RAW.tar 631.2 Mb (http)(custom) TAR (of COV)
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Raw data are available in SRA

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