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Neuron. 2015 Jul 1;87(1):77-94. doi: 10.1016/j.neuron.2015.06.014.

Critical Role of Histone Turnover in Neuronal Transcription and Plasticity.

Author information

1
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.
2
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
3
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5
Department of Neurology, UMass Memorial Medical Center, Worcester, MA 01605, USA.
6
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.
7
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
8
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
9
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.
10
Ansary Stem Cell Institute, Weill Cornell Medical College, New York, NY 10065, USA.
11
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.
12
Center for Accelerator Mass Spectrometry, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA.
13
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.
14
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
15
The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
16
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: c.david.allis@rockefeller.edu.

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.

PMID:
26139371
PMCID:
PMC4491146
DOI:
10.1016/j.neuron.2015.06.014
[Indexed for MEDLINE]
Free PMC Article

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