KAP1-mediated epigenetic repression in the forebrain modulates behavioral vulnerability to stress.
KAP1 is an essential cofactor of KRAB-zinc finger proteins, a family of vertebrate-specific epigenetic repressors of largely unknown functions encoded in the hundreds by the mouse and human genomes. Here, we report that KAP1 is expressed at high levels and necessary for KRAB-mediated repression in mature neurons of the mouse brain. Mice deleted for KAP1 in the adult forebrain exhibit heightened levels of anxiety-like and exploratory activity and stress-induced alterations in spatial learning and memory. In the hippocampus, a small number of genes are dysregulated, including some imprinted genes. Chromatin analyses of the promoters of two genes markedly upregulated in knockout mice reveal decreased histone 3 K9-trimethylation and increased histone 3 and histone 4 acetylation. We propose a model in which the tethering of KAP1-associated chromatin remodeling factors via KRAB-ZFPs epigenetically controls gene expression in the hippocampus, thereby conditioning responses to behavioral stress.
Jakobsson
Johan
J
School of Life Sciences, National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Cordero
Maria Isabel
MI
Bisaz
Reto
R
Groner
Anna C
AC
Busskamp
Volker
V
Bensadoun
Jean-Charles
JC
Cammas
Florence
F
Losson
Régine
R
Mansuy
Isabelle M
IM
Sandi
Carmen
C
Trono
Didier
D
D000107:Acetylation; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008124:Locomotion / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis / Q000379:methods; D008954:Models, Biological; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D016548:Prosencephalon / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology*; D013315:Stress, Psychological / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D000076183:Tripartite Motif-Containing Protein 28; D015854:Up-Regulation / Q000235:genetics*
D006657:Histones; D009687:Nuclear Proteins; D012097:Repressor Proteins; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2