RRC ID 69992
Author Lowden C, Boulet A, Boehler NA, Seecharran S, Rios Garcia J, Lowe NJ, Liu J, Ong JLK, Wang W, Ma L, Cheng AH, Senatore A, Monks DA, Liu BH, Leary SC, Cheng HM.
Title Homeostatic control of nuclear-encoded mitochondrial gene expression by the histone variant H2A.Z is essential for neuronal survival.
Journal Cell Rep
Abstract Histone variants are crucial regulators of chromatin structure and gene transcription, yet their functions within the brain remain largely unexplored. Here, we show that the H2A histone variant H2A.Z is essential for neuronal survival. Mice lacking H2A.Z in GABAergic neurons or Purkinje cells (PCs) present with a progressive cerebellar ataxia accompanied by widespread degeneration of PCs. Ablation of H2A.Z in other neuronal subtypes also triggers cell death. H2A.Z binds to the promoters of key nuclear-encoded mitochondrial genes to regulate their expression and promote organelle function. Bolstering mitochondrial activity genetically or by organelle transplant enhances the survival of H2A.Z-ablated neurons. Changes in bioenergetic status alter H2A.Z occupancy at the promoters of nuclear-encoded mitochondrial genes, an adaptive response essential for cell survival. Our results highlight that H2A.Z fulfills a key, conserved role in neuronal survival by acting as a transcriptional rheostat to regulate the expression of genes critical to mitochondrial function.
Volume 36(11)
Pages 109704
Published 2021-9-14
DOI 10.1016/j.celrep.2021.109704
PII S2211-1247(21)01151-7
PMID 34525369
MeSH Animals Cell Nucleus / metabolism* Cell Survival / drug effects Cells, Cultured Down-Regulation Fibroblasts / cytology Fibroblasts / metabolism GABAergic Neurons / cytology GABAergic Neurons / metabolism Histones / deficiency Histones / genetics* Histones / metabolism Metformin / pharmacology Mice Mice, Inbred C57BL Mice, Knockout Mitochondria / genetics Mitochondria / metabolism* Mitochondrial Proteins / metabolism NF-E2-Related Factor 2 / genetics NF-E2-Related Factor 2 / metabolism Oxidative Phosphorylation Purkinje Cells / cytology Purkinje Cells / metabolism Transcriptome* / drug effects Up-Regulation
IF 8.109
Mice RBRC05765