title: Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition.
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.
authors.affiliation: Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bharadwaj
authors.affiliation: Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Cyril J
authors.initials: CJ
authors.lastname: Peter
authors.affiliation: Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.affiliation: Department of Neurobiology and Behavior, University of California at Irvine, Irvine, CA 92697, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Vogel-Ciernia
authors.affiliation: Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Erica Y
authors.initials: EY
authors.lastname: Shen
authors.affiliation: Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Mitchell
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Mao
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Catheryne
authors.initials: C
authors.lastname: Whittle
authors.affiliation: Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Aslihan
authors.initials: A
authors.lastname: Dincer
authors.affiliation: Max Planck Institute for Psychiatry, 80804 Munich, Germany.
authors.forename: Mira
authors.initials: M
authors.lastname: Jakovcevski
authors.affiliation: Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Venu
authors.initials: V
authors.lastname: Pothula
authors.affiliation: Department of Pharmaceutical Sciences and U.Conn Stem Cell Institute, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Rasmussen
authors.affiliation: Department of Psychiatry, University of Crete, 71003 Iraklion, Greece; Department of Psychology, University of Crete, 71003 Iraklion, Greece.
authors.forename: Stella G
authors.initials: SG
authors.lastname: Giakoumaki
authors.affiliation: 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.
authors.forename: Panos
authors.initials: P
authors.lastname: Bitsios
authors.affiliation: Friedman Brain Institute and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ajfar
authors.initials: A
authors.lastname: Sherif
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Gardner
authors.affiliation: Department of Genetics and Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Subroto
authors.initials: S
authors.lastname: Ghose
authors.affiliation: 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.
authors.forename: Pamela
authors.initials: P
authors.lastname: Sklar
authors.affiliation: 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.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Tamminga
authors.affiliation: Department of Neurology, Boston University, Boston, MA 02118, USA.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Myers
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA 01604, USA.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Futai
authors.affiliation: Department of Neurobiology and Behavior, University of California at Irvine, Irvine, CA 92697, USA.
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Wood
authors.affiliation: 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.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000648:ultrastructure; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D002843:Chromatin; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors