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

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.

Genome-Wide Estrogen Receptor Activity in Breast Cancer

“…Alternatively, this binding profile could suggest NuRD may be required for fine-tuning of gene expression and enhancer functionality, in both ligand-independent and -dependent contexts. Interestingly, CHD4 was recently reported to play an essential role in keeping super-enhancers (ie, clusters of enhancers) open and permissive to the binding of the oncogenic transcription factor PAX3-FOXO1 in rhabdomyosarcoma ( 133 ), suggesting this NuRD component may be a promising target for super-enhancer disruption therapies ( 134 ).…”

CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents

“…MDR1 expression is complicatedly regulated by several important cancer-associated pathways such as RAS/Raf/MEK, JAK/STAT, PI3K/AKT, as well as epigenetic regulators such as histone acetyltransferases, histone deacetylases, etc. [ 55 ] As CHD4/NuRD complex functions as a chromatin remodeler that regulates the accessibility of variable complexes related to gene transcription, and a chromodomain motif in CHD4 does not directly bind to a specific DNA-sequence, CHD4 is more likely to regulate MDR1 expression via complex indirect transcriptional regulation rather than functions as direct transcription factor or enhancer [ 14 , 56 ].Suppression of ERBB signal cascade by CHD4 inhibition could be an example of several potent mechanisms [ 57 ].…”

“…Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a component of the nucleosome remodeling and deacetylase (NuRD) complex. As the name suggests, NuRD complex acts as a chromatin remodeler and CHD4 is considered to play a pivotal role by conferring ATPase activity on the complex [12][13][14]. The NuRD complex is believed to act as a transcription repressor, but recent research indicated that it can also promote gene transcription globally [14,15].…”

“…As the name suggests, NuRD complex acts as a chromatin remodeler and CHD4 is considered to play a pivotal role by conferring ATPase activity on the complex [12][13][14]. The NuRD complex is believed to act as a transcription repressor, but recent research indicated that it can also promote gene transcription globally [14,15]. NuRD or CHD4 is reported to be involved in several important biological functions in cancer cells, such as cell differentiation, cell cycle regulation, and DNA damage repair [16][17][18][19][20][21][22].…”

Epigenetics and Cancer

“…This fusion generates a novel transcription factor with altered transcriptional power and target genes. Surprisingly, although CHD4 is classically defined as a repressor, in FP-RMS it acts as co-activator by interacting with super-enhancers where it generates a chromatin architecture permissive for binding of PAX3-FOXO1 and activating its downstream oncogenic program (Marques et al 2020). These examples further indicate that because of the various cellular functions mediated by chromatin remodeling activities, their readout depend on the cellular or molecular context and cancer type.…”