A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation
Shigeki Iwase,
Emily Brookes,
Saurabh Agarwal,
Aimee I. Badeaux,
Hikaru Ito,
Christina N. Vallianatos,
Giulio Srubek Tomassy,
Tomas Kasza,
Grace Lin,
Andrew Thompson,
Lei Gu,
Kenneth Y. Kwan,
Chinfei Chen,
Maureen A. Sartor,
Brian Egan,
Jun Xu,
Yang Shi
Affiliations
Shigeki Iwase
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; Corresponding author
Emily Brookes
Division of Newborn Medicine, Boston Children’s Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
Saurabh Agarwal
Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USA
Aimee I. Badeaux
Division of Newborn Medicine, Boston Children’s Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
Hikaru Ito
Department of Integrative Physiology and Neuroscience, Washington State University, 1815 Ferdinand’s Lane, Pullman, WA 99164, USA
Christina N. Vallianatos
Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USA
Giulio Srubek Tomassy
Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USA
Tomas Kasza
Department of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USA
Grace Lin
Molecular & Behavioral Neuroscience Institute and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
Andrew Thompson
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
Lei Gu
Division of Newborn Medicine, Boston Children’s Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
Kenneth Y. Kwan
Molecular & Behavioral Neuroscience Institute and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
Chinfei Chen
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
Maureen A. Sartor
Department of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USA
Brian Egan
Active Motif Inc., Carlsbad, CA 92008, USA
Jun Xu
Department of Integrative Physiology and Neuroscience, Washington State University, 1815 Ferdinand’s Lane, Pullman, WA 99164, USA; Corresponding author
Yang Shi
Division of Newborn Medicine, Boston Children’s Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Corresponding author
Summary: 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. : In this study, Iwase et al. characterize Kdm5c-knockout mice to model an important class of intellectual disability. Kdm5c-knockout mice show limited learning, heightened aggression, and dendritic spine defects. Kdm5c is a histone demethylase, and the authors identify altered transcriptional profiles in Kdm5c-knockout brains and investigate the molecular changes in neurons.
