title: Critical Role of Histone Turnover in Neuronal Transcription and Plasticity.
abstract: Turnover and exchange of nucleosomal histones and their variants, a process long believed to be static in post-replicative cells, remains largely unexplored in brain. Here, we describe a novel mechanistic role for HIRA (histone cell cycle regulator) and proteasomal degradation-associated histone dynamics in the regulation of activity-dependent transcription, synaptic connectivity, and behavior. We uncover a dramatic developmental profile of nucleosome occupancy across the lifespan of both rodents and humans, with the histone variant H3.3 accumulating to near-saturating levels throughout the neuronal genome by mid-adolescence. Despite such accumulation, H3.3-containing nucleosomes remain highly dynamic-in a modification-independent manner-to control neuronal- and glial-specific gene expression patterns throughout life. Manipulating H3.3 dynamics in both embryonic and adult neurons confirmed its essential role in neuronal plasticity and cognition. Our findings establish histone turnover as a critical and previously undocumented regulator of cell type-specific transcription and plasticity in mammalian brain.
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA; Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ian.maze@mssm.edu.
authors.forename: Ian
authors.initials: I
authors.lastname: Maze
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Wenderski
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Noh
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Bagot
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Nikos
authors.initials: N
authors.lastname: Tzavaras
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Immanuel
authors.initials: I
authors.lastname: Purushothaman
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Elsässer
authors.affiliation: Department of Neurology, UMass Memorial Medical Center, Worcester, MA 01605, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Neurology, UMass Memorial Medical Center, Worcester, MA 01605, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ionete
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hurd
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Tamminga
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Halene
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Lorna
authors.initials: L
authors.lastname: Farrelly
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Soshnev
authors.affiliation: Ronald O. Perleman and Claudia Cohen Center for Reproductive Medicine, New York, NY 10021, USA; Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Duancheng
authors.initials: D
authors.lastname: Wen
authors.affiliation: Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Birtwistle
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
authors.affiliation: Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Buchholz
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Blitzer
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zuo-Fei
authors.initials: ZF
authors.lastname: Yuan
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
authors.forename: Henrik
authors.initials: H
authors.lastname: Molina
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: c.david.allis@rockefeller.edu.
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002531:Cerebellum / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002843:Chromatin / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D005333:Fetus; D005625:Frontal Lobe / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006624:Hippocampus / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism*; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D002843:Chromatin; D006657:Histones; D009707:Nucleosomes