CLOCK-catalyzed histone H3K37 glutarylation suppresses H3K36 trimethylation pathways in glioblastoma

Circadian CLOCK (circadian locomotor output cycles kaput) can mediate chromatin remodeling events implicated in gene transcription. The acetyltransferase roles of CLOCK are well studied, but CLOCK-mediated chromatin remodeling events are not well understood. We report that CLOCK can use glutaryl-coenzyme A to catalyze glutarylation at histone H3 Lys³⁷ (H3K37glut). H3K37glut is undocumented. The glutaryl moiety of H3K37glut can be pulled by its neighboring H3H39 and H3R40 residues via electrostatic interactions and bent over the pyrrolidine ring of the neighboring H3P38 residue, forming a conformation to block SETD2 binding to the N-terminal tail of histone H3. It reduces SETD2-catalyzed H3K36 trimethylation (H3K36me3) and the H3K36me3-regulated downstream pathways in cells. In glioblastoma, both CLOCK protein and CLOCK-mediated H3K37glut are abnormally up-regulated. H3K37glut significantly correlates with suppressed H3K36me3 level in human glioblastoma tissues, tumor progression, and survival of patients with glioblastoma. This study expands the repertoire of histone modification and diversifies the mechanisms underlying CLOCK-implicated chromatin dynamics. It also unearths an undocumented mechanistic link between dysregulated circadian CLOCK and decreased H3K36me3 pathways in glioblastoma.