Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase <i>KDM5C</i>
Chromatin dysregulation has emerged as a major hallmark of neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). The prevalence of ID and ASD is higher in males compared to females, with unknown mechanisms. Intellectual developmental disorder, X-linke...
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MDPI AG
2023-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/4/637 |
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| author | Katherine M. Bonefas Christina N. Vallianatos Brynne Raines Natalie C. Tronson Shigeki Iwase |
| author_facet | Katherine M. Bonefas Christina N. Vallianatos Brynne Raines Natalie C. Tronson Shigeki Iwase |
| author_sort | Katherine M. Bonefas |
| collection | DOAJ |
| description | Chromatin dysregulation has emerged as a major hallmark of neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). The prevalence of ID and ASD is higher in males compared to females, with unknown mechanisms. Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (MRXSCJ), is caused by loss-of-function mutations of lysine demethylase 5C (<i>KDM5C</i>), a histone H3K4 demethylase gene. KDM5C escapes X-inactivation, thereby presenting at a higher level in females. Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous <i>KDM5C</i> mutations can show cognitive deficits. The mouse model of MRXSCJ, male <i>Kdm5c</i>-hemizygous knockout animals, recapitulates key features of human male patients. However, the behavioral and molecular traits of <i>Kdm5c</i>-heterozygous female mice remain incompletely characterized. Here, we report that gene expression and behavioral abnormalities are readily detectable in <i>Kdm5c</i>-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females. Furthermore, we found both shared and sex-specific consequences of a reduced KDM5C dose in social behavior, gene expression, and genetic interaction with the counteracting enzyme KMT2A. These observations provide an essential insight into the sex-biased manifestation of neurodevelopmental disorders and sex chromosome evolution. |
| first_indexed | 2024-03-11T09:00:44Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T09:00:44Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj.art-3e5e49bdb2cf4af8b6d460e06623ff2c2023-11-16T19:45:08ZengMDPI AGCells2073-44092023-02-0112463710.3390/cells12040637Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase <i>KDM5C</i>Katherine M. Bonefas0Christina N. Vallianatos1Brynne Raines2Natalie C. Tronson3Shigeki Iwase4Department of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USADepartment of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USADepartment of Psychology, College of LS&A, University of Michigan, Ann Arbor, MI 48109, USANeuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USADepartment of Human Genetics, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USAChromatin dysregulation has emerged as a major hallmark of neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorders (ASD). The prevalence of ID and ASD is higher in males compared to females, with unknown mechanisms. Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type (MRXSCJ), is caused by loss-of-function mutations of lysine demethylase 5C (<i>KDM5C</i>), a histone H3K4 demethylase gene. KDM5C escapes X-inactivation, thereby presenting at a higher level in females. Initially, MRXSCJ was exclusively reported in males, while it is increasingly evident that females with heterozygous <i>KDM5C</i> mutations can show cognitive deficits. The mouse model of MRXSCJ, male <i>Kdm5c</i>-hemizygous knockout animals, recapitulates key features of human male patients. However, the behavioral and molecular traits of <i>Kdm5c</i>-heterozygous female mice remain incompletely characterized. Here, we report that gene expression and behavioral abnormalities are readily detectable in <i>Kdm5c</i>-heterozygous female mice, demonstrating the requirement for a higher KDM5C dose in females. Furthermore, we found both shared and sex-specific consequences of a reduced KDM5C dose in social behavior, gene expression, and genetic interaction with the counteracting enzyme KMT2A. These observations provide an essential insight into the sex-biased manifestation of neurodevelopmental disorders and sex chromosome evolution.https://www.mdpi.com/2073-4409/12/4/637chromatin regulatorsx-linked intellectual disabilitylearning and memoryneurodevelopmental disordershistone demethylase |
| spellingShingle | Katherine M. Bonefas Christina N. Vallianatos Brynne Raines Natalie C. Tronson Shigeki Iwase Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase <i>KDM5C</i> Cells chromatin regulators x-linked intellectual disability learning and memory neurodevelopmental disorders histone demethylase |
| title | Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase <i>KDM5C</i> |
| title_full | Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase <i>KDM5C</i> |
| title_fullStr | Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase <i>KDM5C</i> |
| title_full_unstemmed | Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase <i>KDM5C</i> |
| title_short | Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase <i>KDM5C</i> |
| title_sort | sexually dimorphic alterations in the transcriptome and behavior with loss of histone demethylase i kdm5c i |
| topic | chromatin regulators x-linked intellectual disability learning and memory neurodevelopmental disorders histone demethylase |
| url | https://www.mdpi.com/2073-4409/12/4/637 |
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