GSBS Student Publications

Title

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

Student Author(s)

Rahul Bharadwaj

GSBS Program

Interdisciplinary Graduate Program

UMMS Affiliation

Department of Psychiatry; Brudnick Neuropsychiatric Research Institute

Date

12-3-2014

Document Type

Article

Medical Subject Headings

Aged; Aged, 80 and over; Animals; Animals, Newborn; Antipsychotic Agents; Cells, Cultured; Cerebral Cortex; Chromatin; Cognition; Female; Gene Expression Regulation; HEK293 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Neurons; Polymorphism, Single Nucleotide; Receptors, N-Methyl-D-Aspartate; Schizophrenia; Signal Transduction; Transcription Factors

Disciplines

Genetics and Genomics | Neuroscience and Neurobiology

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.

Rights and Permissions

Citation: 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 site

DOI of Published Version

10.1016/j.neuron.2014.10.032

Related Resources

Link to Article in PubMed

Journal Title

Neuron

PubMed ID

25467983