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Neuron. 2014 Dec 3;84(5):997-1008. doi: 10.1016/j.neuron.2014.10.032. Epub 2014 Nov 13.

Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition.

Author information

1
Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2
Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; James J. Peters Veterans Affairs Medical Center, Bronx, New York, NY 10468, USA.
3
Department of Neurobiology and Behavior, University of California at Irvine, Irvine, CA 92697, USA.
4
Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
5
Max Planck Institute for Psychiatry, 80804 Munich, Germany.
6
Department of Pharmaceutical Sciences and U.Conn Stem Cell Institute, University of Connecticut, Storrs, CT 06269, USA.
7
Department of Psychiatry, University of Crete, 71003 Iraklion, Greece; Department of Psychology, University of Crete, 71003 Iraklion, Greece.
8
Computational Medicine Laboratory, Institute of Computer Science, Foundation for Research and Technology Hellas, 71003 Iraklion, Greece; Department of Psychiatry, University of Crete, 71003 Iraklion, Greece.
9
Department of Genetics and Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
10
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
11
Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
12
Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; James J. Peters Veterans Affairs Medical Center, Bronx, New York, NY 10468, USA.
13
Department of Neurology, Boston University, Boston, MA 02118, USA.
14
Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: schahram.akbarian@mssm.edu.

Abstract

Three-dimensional chromosomal conformations regulate transcription by moving enhancers and regulatory elements into spatial proximity with target genes. Here we describe activity-regulated long-range loopings bypassing up to 0.5 Mb of linear genome to modulate NMDA glutamate receptor GRIN2B expression in human and mouse prefrontal cortex. Distal intronic and 3' intergenic loop formations competed with repressor elements to access promoter-proximal sequences, and facilitated expression via a "cargo" of AP-1 and NRF-1 transcription factors and TALE-based transcriptional activators. Neuronal deletion or overexpression of Kmt2a/Mll1 H3K4- and Kmt1e/Setdb1 H3K9-methyltransferase was associated with higher-order chromatin changes at distal regulatory Grin2b sequences and impairments in working memory. Genetic polymorphisms and isogenic deletions of loop-bound sequences conferred liability for cognitive performance and decreased GRIN2B expression. Dynamic regulation of chromosomal conformations emerges as a novel layer for transcriptional mechanisms impacting neuronal signaling and cognition.

PMID:
25467983
PMCID:
PMC4258154
DOI:
10.1016/j.neuron.2014.10.032
[Indexed for MEDLINE]
Free PMC Article

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