NuRD subunit CHD4 regulates super-enhancer accessibility in rhabdomyosarcoma and represents a general tumor dependency

Open access
Date
2020Type
- Journal Article
Citations
Cited 13 times in
Web of Science
Cited 13 times in
Scopus
ETH Bibliography
yes
Altmetrics
Abstract
The NuRD complex subunit CHD4 is essential for fusion-positive rhabdomyosarcoma (FP-RMS) survival, but the mechanisms underlying this dependency are not understood. Here, a NuRD-specific CRISPR screen demonstrates that FP-RMS is particularly sensitive to CHD4 amongst the NuRD members. Mechanistically, NuRD complex containing CHD4 localizes to super-enhancers where CHD4 generates a chromatin architecture permissive for the binding of the tumor driver and fusion protein PAX3-FOXO1, allowing downstream transcription of its oncogenic program. Moreover, CHD4 depletion removes HDAC2 from the chromatin, leading to an increase and spread of histone acetylation, and prevents the positioning of RNA Polymerase 2 at promoters impeding transcription initiation. Strikingly, analysis of genome-wide cancer dependency databases identifies CHD4 as a general cancer vulnerability. Our findings describe CHD4, a classically defined repressor, as positive regulator of transcription and super-enhancer accessibility as well as establish this remodeler as an unexpected broad tumor susceptibility and promising drug target for cancer therapy. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000438609Publication status
publishedExternal links
Journal / series
eLifeVolume
Pages / Article No.
Publisher
eLife Sciences PublicationsMore
Show all metadata
Citations
Cited 13 times in
Web of Science
Cited 13 times in
Scopus
ETH Bibliography
yes
Altmetrics