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Mutations in a number of chromatin modifiers are associated with human neurological disorders. KDM5C, a histone H3 lysine 4 di- and tri-methyl (H3K4me2/3)-specific demethylase, is frequently mutated in X-linked intellectual disability (XLID) patients. Here, we report that disruption of the mouse Kdm5c gene recapitulates adaptive and cognitive abnormalities observed in XLID, including impaired social behavior, memory deficits, and aggression. Kdm5c-knockout brains exhibit abnormal dendritic arborization, spine anomalies, and altered transcriptomes. In neurons, Kdm5c is recruited to promoters that harbor CpG islands decorated with high levels of H3K4me3, where it fine-tunes H3K4me3 levels. Kdm5c predominantly represses these genes, which include members of key pathways that regulate the development and function of neuronal circuitries. In summary, our mouse behavioral data strongly suggest that KDM5C mutations are causal to XLID. Furthermore, our findings suggest that loss of KDM5C function may impact gene expression in multiple regulatory pathways relevant to the clinical phenotypes.

Original publication

DOI

10.1016/j.celrep.2015.12.091

Type

Journal article

Journal

Cell Reports

Publication Date

02/2016

Volume

14

Pages

1000 - 1009

Addresses

Division of Newborn Medicine, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USA. Electronic address: siwase@umich.edu.

Keywords

Brain, Dendritic Spines, Animals, Mice, Knockout, Disease Models, Animal, Oxidoreductases, N-Demethylating, Lysine, Histones, Aggression, Social Behavior, Memory, Transcription, Genetic, Gene Expression Regulation, CpG Islands, Methylation, Genes, X-Linked, Promoter Regions, Genetic, Intellectual Disability