chromIDEAS reveals epigenetic dynamics via multi-dimensional clustering of chromatin states.

Cancer-related transcriptional dysregulation involves complex, incompletely understood epigenetic mechanisms. Chromatin states (CSs), defined by recurrent co-occurrence patterns of epigenetic marks, provide a comprehensive view for epigenomic landscape. However, current CS analyses often produce excessive subtly distinct states, making functional interpretation difficult. Building on single-cell clustering principles, we developed chromIDEAS to overcome this challenge. Recognizing that epigenetic function is context-dependent, chromIDEAS groups CSs into functionally coherent clusters by jointly analyzing their epigenetic composition and genomic distribution. When applying to THP1 leukemia and CD34+ cells, chromIDEAS consistently identified five CS clusters (CSCs) preserved across both cell types, exhibiting distinct functional coherence. These CSCs captured core transcriptional states (active and repressive) and key genomic compartments (promoters, gene bodies, and TES). Notably, differential CSC analysis revealed that Wnt signaling activation in THP1 cells, a hallmark of leukemogenesis, is mediated by KDM4A-dependent removal of repressive states. Mechanistically, KDM4A depletion restored repressive states on Wnt signaling and impaired proliferation, while WNT10B overexpression effectively rescued this phenotype. Our work establishes chromIDEAS as a pioneering tool for functional CS annotation and uncovers KDM4A-mediated epigenetic derepression in leukemia pathogenesis. These findings highlight critical role of CSs in mechanistic studies and introduce a novel paradigm for epigenetic exploration.