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

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

  • Sci Adv. 2026 Mar 27;12(13):eaea1127. doi: 10.1126/sciadv.aea1127.
Yu Wang 1,  Runxin Zhou 1,  Xiao Zeng 1,  Dingyuan Guo 1,  Nan Li 1,  Shuangli Li 2,  Xu Zhang 2,  Mingxuan Shi 1,  Li Jiang 3 4,  Mingzhu Fan 5 6,  Shan Feng 5 6,  Lili He 7,  Anbing Shi 1 8,  Ke Liu 9,  Yusong R Guo 1 8,  Lichun He 2,  Mingchang Li 3,  Yugang Wang 1 8
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
  • 2 National Centre for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, China.
  • 3 Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China.
  • 4 Department of Neurology, The Affiliated Nanhua Hospital, University of South China, Hengyang 421001, China.
  • 5 Mass Spectrometry & Metabolomics Core Facility, The Biomedical Research Core Facility, Center for Research Equipment and Facilities, Westlake University, Hangzhou 310024, China.
  • 6 Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China.
  • 7 Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 8 Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
  • 9 Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan 250000, China.
PMID: 41880493 DOI: 10.1126/sciadv.aea1127
Abstract

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.

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