CHD4 remodels cellular chromatin accessibility and activates c-Myc pathway via phase separation in multiple myeloma

Multiple myeloma (MM) is an incurable hematologic malignancy, which is inherently related to chromatin abnormalities. Chromatin remodeling factors play an important role in the regulation of chromatin abnormalities, among which chromodomain-helicase-DNA-binding protein 4 (CHD4) was positive-associated with poor outcomes in MM patients and an elevated level of CHD4 promoted MM cell proliferation. Mechanistically, CHD4 untwisted c-Myc G4 and regulated chromatin accessibility through ATPase domain. Additionally, CHD4 recruited c-Myc though chromatin domain and stabilized c-Myc to chromatin by liquid–liquid phase separation, which up-regulated the expression of c-Myc. Furthermore, Luteolin 7-O-glucuronide and Idarubicin were identified as potential drugs targeting ATPase domain and chromatin domain for MM by a de novo design. Our study highlights the role of CHD4 as a high-risk gene in MM and suggests that remodels cellular chromatin accessibility and activates c-Myc pathway via phase separation in MM. RNA-sequencing (mRNA-seq) to determine the changes of transcription factor expression in MM Ctrl and CHD4-KD cells and found that the knockdown of CHD4 down-regulated the expression