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Conserved higher-order chromatin regulates NMDA receptor gene expression and cognition
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Authors
Bharadwaj, RahulPeter, Cyril J.
Jiang, Yan
Roussos, Panos
Vogel-Ciernia, Annie
Shen, Erica Y.
Mitchell, Amanda C.
Mao, Wenjie
Whittle, Catheryne
Dincer, Aslihan
Jakovcevski, Mira
Pothula, Venu
Rasmussen, Theodore P.
Giakoumaki, Stella G.
Bitsios, Panos
Sherif, Ajfar
Gardner, Paul D.
Ernst, Patricia
Ghose, Subroto
Sklar, Pamela
Haroutunian, Vahram
Tamminga, Carol
Myers, Richard H.
Futai, Kensuke
Wood, Marcelo A.
Akbarian, Schahram
Student Authors
Rahul BharadwajWenjie Mao
Academic Program
NeuroscienceUMass Chan Affiliations
Gardner LabBrudnick Neuropsychiatric Research Institute
Department of Psychiatry
Futai Lab
Morningside Graduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2014-12-03
Metadata
Show full item recordAbstract
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.Source
Neuron. 2014 Dec 3;84(5):997-1008. doi: 10.1016/j.neuron.2014.10.032. Epub 2014 Nov 13. Link to article on publisher's siteDOI
10.1016/j.neuron.2014.10.032Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33386PubMed ID
25467983Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.neuron.2014.10.032