Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus
Gilda Stefanelli,
Amber B. Azam,
Brandon J. Walters,
Mark A. Brimble,
Caroline P. Gettens,
Pascale Bouchard-Cannon,
Hai-Ying M. Cheng,
Andrew M. Davidoff,
Klotilda Narkaj,
Jeremy J. Day,
Andrew J. Kennedy,
Iva B. Zovkic
Affiliations
Gilda Stefanelli
Department of Psychology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada
Amber B. Azam
Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G3, Canada
Brandon J. Walters
Department of Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON M5G OA4, Canada
Mark A. Brimble
Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Department of Hematology, University College London Cancer Institute, London, WC1E 6BT, UK
Caroline P. Gettens
Department of Chemistry and Biochemistry, Bates College, Lewiston, ME 04240, USA
Pascale Bouchard-Cannon
Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G3, Canada
Hai-Ying M. Cheng
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada
Andrew M. Davidoff
Department of Surgery, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Klotilda Narkaj
Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G3, Canada
Jeremy J. Day
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35233, USA
Andrew J. Kennedy
Department of Chemistry and Biochemistry, Bates College, Lewiston, ME 04240, USA; Corresponding author
Iva B. Zovkic
Department of Psychology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G3, Canada; Corresponding author
Summary: Histone variants were recently discovered to regulate neural plasticity, with H2A.Z emerging as a memory suppressor. Using whole-genome sequencing of the mouse hippocampus, we show that basal H2A.Z occupancy is positively associated with steady-state transcription, whereas learning-induced H2A.Z removal is associated with learning-induced gene expression. AAV-mediated H2A.Z depletion enhanced fear memory and resulted in gene-specific alterations of learning-induced transcription, reinforcing the role of H2A.Z as a memory suppressor. H2A.Z accumulated with age, although it remained sensitive to learning-induced eviction. Learning-related H2A.Z removal occurred at largely distinct genes in young versus aged mice, suggesting that H2A.Z is subject to regulatory shifts in the aged brain despite similar memory performance. When combined with prior evidence of H3.3 accumulation in neurons, our data suggest that nucleosome composition in the brain is reorganized with age. : Stefanelli et al. find that the histone variant H2A.Z accumulates with age in the hippocampus and that learning results in H2A.Z removal from distinct genes in young and aged mice despite similar levels of memory formation. These data suggest that replication-independent histone variants become overrepresented in neural chromatin during aging. Keywords: H2A.Z, fear conditioning, memory, ChIP-seq, RNA-seq, gene expression, epigenetics, chromatin, hippocampus, histone variants
