title: Neuronal necrosis is regulated by a conserved chromatin-modifying cascade.
abstract: Neuronal necrosis induced by calcium overload causes devastating brain dysfunction in diseases such as stroke and brain trauma. It has been considered a stochastic event lacking genetic regulation, and pharmacological means to suppress neuronal necrosis are lacking. Using a Drosophila model of calcium overloading, we found JIL-1/mitogen- and stress-activated protein kinase 1/2 is a regulator of neuronal necrosis through phosphorylation of histone H3 serine 28 (H3S28ph). Further, we identified its downstream events including displacement of polycomb repressive complex 1 (PRC1) and activation of Trithorax (Trx). To test the role of JIL-1/PRC1/Trx cascade in mammals, we studied the necrosis induced by glutamate in rat cortical neuron cultures and rodent models of brain ischemia and found the cascade is activated in these conditions and inhibition of the cascade suppresses necrosis in vitro and in vivo. Together, our research demonstrates that neuronal necrosis is regulated by a chromatin-modifying cascade, and this discovery may provide potential therapeutic targets and biomarkers for neuronal necrosis.
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Kai
authors.initials: K
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Lianggong
authors.initials: L
authors.lastname: Ding
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China; Howard Hughes Medical Institute, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Chunyue
authors.initials: C
authors.lastname: Zhao
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Ye
authors.initials: Y
authors.lastname: Lei
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Shuting
authors.initials: S
authors.lastname: Han
authors.affiliation: The Education Ministry Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing 100871, China;
authors.forename: Wei
authors.initials: W
authors.lastname: Tao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Research Center for Bone and Stem Cells, Department of Anatomy, Nanjing Medical University, Nanjing, Jiangsu 210029 China;
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
authors.affiliation: Howard Hughes Medical Institute, Strang Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, New York, NY 10065; and.
authors.forename: Hermann
authors.initials: H
authors.lastname: Steller
authors.affiliation: Howard Hughes Medical Institute, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242; michael-welsh@uiowa.edu leiliu@pku.edu.cn.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.affiliation: The State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing 100871, China; Beijing Institute for Brain Disorders, Department of Neurobiology, Capital Medical University, Youanmen, Beijing 100069, China michael-welsh@uiowa.edu leiliu@pku.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism* / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009336:Necrosis; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D063146:Polycomb-Group Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D029721:Drosophila Proteins; D006657:Histones; D063146:Polycomb-Group Proteins; C512571:trx protein, Drosophila; C507306:JIL-1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium
keywords: H3K4me3; aging; epigenetics; histone modification; neurodegeneration