A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124715015478 |
| _version_ | 1818522026694934528 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shigeki Iwase |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T05:27:55Z |
| format | Article |
| id | doaj.art-8cb12d3238124adfb25be55f9e66ebd4 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T05:27:55Z |
| publishDate | 2016-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-8cb12d3238124adfb25be55f9e66ebd42022-12-22T01:19:31ZengElsevierCell Reports2211-12472016-02-0114510001009A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone MethylationShigeki Iwase0Emily Brookes1Saurabh Agarwal2Aimee I. Badeaux3Hikaru Ito4Christina N. Vallianatos5Giulio Srubek Tomassy6Tomas Kasza7Grace Lin8Andrew Thompson9Lei Gu10Kenneth Y. Kwan11Chinfei Chen12Maureen A. Sartor13Brian Egan14Jun Xu15Yang Shi16Division 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 authorDivision of Newborn Medicine, Boston Children’s Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USADepartment of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USADivision of Newborn Medicine, Boston Children’s Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USADepartment of Integrative Physiology and Neuroscience, Washington State University, 1815 Ferdinand’s Lane, Pullman, WA 99164, USADepartment of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USADepartment of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Avenue, Cambridge, MA 02138, USADepartment of Human Genetics, University of Michigan, 5815 Medical Science II, Ann Arbor, MI 48109, USAMolecular & Behavioral Neuroscience Institute and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USADepartment of Neurology, F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USADivision of Newborn Medicine, Boston Children’s Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USAMolecular & Behavioral Neuroscience Institute and Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USADepartment of Neurology, F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USADepartment of Computational Medicine and Bioinformatics, University of Michigan, 100 Washtenaw Avenue, Ann Arbor, MI 48109, USAActive Motif Inc., Carlsbad, CA 92008, USADepartment of Integrative Physiology and Neuroscience, Washington State University, 1815 Ferdinand’s Lane, Pullman, WA 99164, USA; Corresponding authorDivision of Newborn Medicine, Boston Children’s Hospital and Department of Cell Biology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124715015478 |
| spellingShingle | 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 A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation Cell Reports |
| title | A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation |
| title_full | A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation |
| title_fullStr | A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation |
| title_full_unstemmed | A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation |
| title_short | A Mouse Model of X-linked Intellectual Disability Associated with Impaired Removal of Histone Methylation |
| title_sort | mouse model of x linked intellectual disability associated with impaired removal of histone methylation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124715015478 |
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