title: A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation.
abstract: 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.
authors.affiliation: 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.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Iwase
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Brookes
authors.affiliation: Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Aimee I
authors.initials: AI
authors.lastname: Badeaux
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University, 1815 Ferdinand's Lane, Pullman, WA 99164, USA.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USA.
authors.forename: Christina N
authors.initials: CN
authors.lastname: Vallianatos
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA.
authors.forename: Giulio Srubek
authors.initials: GS
authors.lastname: Tomassy
authors.affiliation: Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kasza
authors.affiliation: Molecular & Behavioral Neuroscience Institute and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Lin
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: Molecular & Behavioral Neuroscience Institute and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Kwan
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Chinfei
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Sartor
authors.affiliation: Active Motif Inc., Carlsbad, CA 92008, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Egan
authors.affiliation: Department of Integrative Physiology and Neuroscience, Washington State University, 1815 Ferdinand's Lane, Pullman, WA 99164, USA. Electronic address: junxu@vetmed.wsu.edu.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Division of Newborn Medicine, Boston Children's Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: yshi@hms.harvard.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000374:Aggression; D000818:Animals; D001921:Brain / Q000473:pathology; D018899:CpG Islands; D049229:Dendritic Spines / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D050172:Genes, X-Linked; D056466:Histone Demethylases; D006657:Histones / Q000378:metabolism*; D008607:Intellectual Disability / Q000235:genetics*; D008239:Lysine / Q000378:metabolism; D008568:Memory; D008745:Methylation; D018345:Mice, Knockout; D010089:Oxidoreductases, N-Demethylating / Q000172:deficiency / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012919:Social Behavior; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D056466:Histone Demethylases; C490173:Kdm5c protein, mouse; D010089:Oxidoreductases, N-Demethylating; D008239:Lysine