2. Academic Validation
  3. Metabolically controlled histone H4K5 acylation/acetylation ratio drives BRD4 genomic distribution

Metabolically controlled histone H4K5 acylation/acetylation ratio drives BRD4 genomic distribution

  • Cell Rep. 2021 Jul 27;36(4):109460. doi: 10.1016/j.celrep.2021.109460.
Mengqing Gao 1,  Jin Wang 2,  Sophie Rousseaux 3,  Minjia Tan 4,  Lulu Pan 4,  Lijun Peng 2,  Sisi Wang 2,  Wenqian Xu 2,  Jiayi Ren 2,  Yuanfang Liu 5,  Martin Spinck 6,  Sophie Barral 3,  Tao Wang 3,  Florent Chuffart 3,  Ekaterina Bourova-Flin 3,  Denis Puthier 7,  Sandrine Curtet 3,  Lisa Bargier 7,  Zhongyi Cheng 8,  Heinz Neumann 6,  Jian Li 9,  Yingming Zhao 10,  Jian-Qing Mi 11,  Saadi Khochbin 12
Affiliations

Affiliations

  • 1 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; CNRS UMR 5309/INSERM U1209/Université Grenoble-Alpes/Institute for Advanced Biosciences, 38706 La Tronche, France; Pôle Franco-Chinois de Recherche en Sciences du Vivant et Génomique, 200025 Shanghai, China.
  • 2 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; Pôle Franco-Chinois de Recherche en Sciences du Vivant et Génomique, 200025 Shanghai, China.
  • 3 CNRS UMR 5309/INSERM U1209/Université Grenoble-Alpes/Institute for Advanced Biosciences, 38706 La Tronche, France; Pôle Franco-Chinois de Recherche en Sciences du Vivant et Génomique, 200025 Shanghai, China.
  • 4 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, 201203 Shanghai, China.
  • 5 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
  • 6 Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.
  • 7 Aix Marseille Université, INSERM, TAGC, TGML, 13288 Marseille, France.
  • 8 Jingjie PTM Biolab (Hangzhou), 310018 Hangzhou, China.
  • 9 Clinical Research Center, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
  • 10 Ben May Department of Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
  • 11 Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; Pôle Franco-Chinois de Recherche en Sciences du Vivant et Génomique, 200025 Shanghai, China. Electronic address: jianqingmi@shsmu.edu.cn.
  • 12 CNRS UMR 5309/INSERM U1209/Université Grenoble-Alpes/Institute for Advanced Biosciences, 38706 La Tronche, France; Pôle Franco-Chinois de Recherche en Sciences du Vivant et Génomique, 200025 Shanghai, China. Electronic address: saadi.khochbin@univ-grenoble-alpes.fr.
PMID: 34320364 DOI: 10.1016/j.celrep.2021.109460
Abstract

In addition to acetylation, histones are modified by a series of competing longer-chain acylations. Most of these acylation marks are enriched and co-exist with acetylation on active gene regulatory elements. Their seemingly redundant functions hinder our understanding of histone acylations' specific roles. Here, by using an acute lymphoblastic leukemia (ALL) cell model and blasts from individuals with B-precusor ALL (B-ALL), we demonstrate a role of mitochondrial activity in controlling the histone acylation/acetylation ratio, especially at histone H4 lysine 5 (H4K5). An increase in the ratio of non-acetyl acylations (crotonylation or butyrylation) over acetylation on H4K5 weakens bromodomain containing protein 4 (BRD4) bromodomain-dependent chromatin interaction and enhances BRD4 nuclear mobility and availability for binding transcription start site regions of active genes. Our data suggest that the metabolism-driven control of the histone acetylation/longer-chain acylation(s) ratio could be a common mechanism regulating the bromodomain factors' functional genomic distribution.

Figures
Products