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

Rahul Bharadwaj, Cyril J. Peter, Yan Jiang, Panos Roussos, Annie Vogel-Ciernia, Erica Y. Shen, Amanda C. Mitchell, Wenjie Mao, Catheryne Whittle, Aslihan Dincer, Mira Jakovcevski, Venu Pothula, Theodore P. Rasmussen, Stella G. Giakoumaki, Panos Bitsios, Ajfar Sherif, Paul D. Gardner, Patricia Ernst, Subroto Ghose, Pamela SklarVahram Haroutunian, Carol Tamminga, Richard H. Myers, Kensuke Futai, Marcelo A. Wood, Schahram Akbarian

Research output: Contribution to journalArticlepeer-review

64 Scopus citations


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.

Original languageEnglish
Pages (from-to)997-1008
Number of pages12
Issue number5
StatePublished - 3 Dec 2014


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