Necrotic cell death is mediated by a specific chromatin-modifying pathway in fly and mammals. Kai Liu¹, Yuhong Li¹, Lianggong Ding¹, Hui Yang¹, Chunyue Zhao¹, Hermann Steller², Lei Liu¹. 1) State Key Lab of Biomembrane and Membrane Biotechnology, School of Life Sciences, Peking University, Beijing, China; 2) Strang Laboratory of Apoptosis and Cancer Biology, Howard Hughes Medical Institute, The Rockefeller University, NY.

   Necrotic cell death (necrosis) plays important roles in many neurological diseases such as ischemic stroke, epilepsy and traumatic brain injury. Neuronal necrosis often results from acute calcium overload through glutamate receptors. However, the mechanism of necrosis execution is largely unknown. By genetic modeling calcium-overload-induced neuronal necrosis in Drosophila, we discovered specific chromatin changes in necrosis, including increased Histone H3 Serine 28 phosphorylation (H3S28ph), dissociation of polycomb repressive complex 1 (PRC1) from chromatin and increased H3 lysine 4 trimethylation (H3K4me3). Importantly, mutants of PRC1 enhance necrosis, whereas mutants of JIL-1 (the kinase generating H3S28ph to repel PRC1) and Trx (the histone methyltransferase generating H3K4me3 to antagonize PRC1) suppress necrosis. These results indicate neuronal necrosis is mediated by a chromatin-modifying pathway involving phosphorylation of H3S28 by JIL-1 to repel PRC1 and activate Trx. Moreover, we found this pathway mediates necrosis through mitochondrial fragmentation. Strikingly, this pathway is also activated in glutamate-induced necrosis in rat cortical neurons and ischemic mouse brains, and inhibition of the pathway suppresses neuronal necrosis in vitro and in vivo. These findings uncover a novel conserved mechanism of necrosis execution involving nucleus response and subsequent signal transduction to mitochondria, which provides promising drug targets and novel markers for necrosis-related diseases.