@article{e47cfdde36b44955976c3d838492cebc,
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.",
author = "Rahul Bharadwaj and Peter, {Cyril J.} and Yan Jiang and Panos Roussos and Annie Vogel-Ciernia and Shen, {Erica Y.} and Mitchell, {Amanda C.} and Wenjie Mao and Catheryne Whittle and Aslihan Dincer and Mira Jakovcevski and Venu Pothula and Rasmussen, {Theodore P.} and Giakoumaki, {Stella G.} and Panos Bitsios and Ajfar Sherif and Gardner, {Paul D.} and Patricia Ernst and Subroto Ghose and Pamela Sklar and Vahram Haroutunian and Carol Tamminga and Myers, {Richard H.} and Kensuke Futai and Wood, {Marcelo A.} and Schahram Akbarian",
note = "Funding Information: This work was supported by National Institute of Mental Health grants R01 MH086509 and P50 MH096890 (S.A.); National Institute of Neurological Disorders and Stroke grant R01 NS073947-04 (R.H.M.); National Institute of Drug Abuse grant R01 DA036984 (M.A.W. and S.A.); NIH Brain and Tissue Repository grant HHSN271201300031C and the VA, and Veterans Affairs Merit grant BX002395, BBRF, the APA-Merck & Co. Early Academic Career Research Award (P.R.); the Connecticut State Stem Cell Research Program (09-SCB-UCON-18) (T.P.R.); the Whitehall Foundation (K.F.); and the University of Crete Research Funds Account (E.L.K.E.1348). The authors thank the participants and the personnel of the Military Training Camp of Candidate, Supply Army officers (SEAP) in Heraklion, Crete, for their help with the LOGOS study. Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",
year = "2014",
month = dec,
day = "3",
doi = "10.1016/j.neuron.2014.10.032",
language = "English",
volume = "84",
pages = "997--1008",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",
}