Homeostatic control of nuclear-encoded mitochondrial gene expression by the histone variant H2A.Z is essential for neuronal survival
Christopher Lowden,
Aren Boulet,
Nicholas A. Boehler,
Shavanie Seecharran,
Julian Rios Garcia,
Nicholas J. Lowe,
Jiashu Liu,
Jonathan L.K. Ong,
Wanzhang Wang,
Lingfeng Ma,
Arthur H. Cheng,
Adriano Senatore,
D. Ashley Monks,
Bao-hua Liu,
Scot C. Leary,
Hai-Ying Mary Cheng
Affiliations
Christopher Lowden
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
Aren Boulet
Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Nicholas A. Boehler
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
Shavanie Seecharran
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
Julian Rios Garcia
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
Nicholas J. Lowe
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada
Jiashu Liu
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
Jonathan L.K. Ong
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada
Wanzhang Wang
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada
Lingfeng Ma
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada
Arthur H. Cheng
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
Adriano Senatore
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
D. Ashley Monks
Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Department of Psychology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada
Bao-hua Liu
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
Scot C. Leary
Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
Hai-Ying Mary Cheng
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Corresponding author
Summary: 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.
