Setdb1 histone methyltransferase regulates mood-related behaviors and expression of the NMDA receptor subunit NR2B.
Histone methyltransferases specific for the histone H3-lysine 9 residue, including Setdb1 (Set domain, bifurcated 1)/Eset/Kmt1e are associated with repressive chromatin remodeling and expressed in adult brain, but potential effects on neuronal function and behavior remain unexplored. Here, we report that transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair, and learned helplessness. Chromatin immunoprecipitation in conjunction with DNA tiling arrays (ChIP-chip) revealed that genomic occupancies of neuronal Setdb1 are limited to <1% of annotated genes, which include the NMDA receptor subunit NR2B/Grin2B and other ionotropic glutamate receptor genes. Chromatin conformation capture and Setdb1-ChIP revealed a loop formation tethering the NR2B/Grin2b promoter to the Setdb1 target site positioned 30 kb downstream of the transcription start site. In hippocampus and ventral striatum, two key structures in the neuronal circuitry regulating mood-related behaviors, Setdb1-mediated repressive histone methylation at NR2B/Grin2b was associated with decreased NR2B expression and EPSP insensitivity to pharmacological blockade of NR2B, and accelerated NMDA receptor desensitization consistent with a shift in NR2A/B subunit ratios. In wild-type mice, systemic treatment with the NR2B antagonist, Ro25-6981 [R-(R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidine propranol], and hippocampal small interfering RNA-mediated NR2B/Grin2b knockdown resulted in behavioral changes similar to those elicited by the Setdb1 transgene. Together, these findings point to a role for neuronal Setdb1 in the regulation of affective and motivational behaviors through repressive chromatin remodeling at a select set of target genes, resulting in altered NMDA receptor subunit composition and other molecular adaptations.
Jiang
Yan
Y
Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
Jakovcevski
Mira
M
Bharadwaj
Rahul
R
Connor
Caroline
C
Schroeder
Frederick A
FA
Lin
Cong L
CL
Straubhaar
Juerg
J
Martin
Gilles
G
Akbarian
Schahram
S
D000221:Adaptation, Ocular / Q000187:drug effects / Q000235:genetics; D000339:Affect / Q000187:drug effects / Q000502:physiology*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004597:Electroshock / Q000009:adverse effects; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005518:Food Preferences / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D046353:Immobility Response, Tonic / Q000187:drug effects / Q000502:physiology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques / Q000379:methods; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D014162:Transfection / Q000379:methods
D002843:Chromatin; D018683:Excitatory Amino Acid Agents; C121001:NR2B NMDA receptor; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D013549:Sweetening Agents; D049452:Green Fluorescent Proteins; D013395:Sucrose; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2