In this proposal, I address the role of the histone demethylase KDM6A in the regulation of sexually dimorphic gene expression during neuronal differentiation. KDM6A removes a repressive histone mark (H3K27me3) from chromatin, which results in gene activation. KDM6A is encoded by a gene that escapes X inactivation, resulting in higher expression in females. Many behavioral and psychiatric phenotypes are influenced by aberrant epigenetic modifications. Some of these phenotypes manifest in a sex-specific manner, for example depression is more common in females. The sex-specific differences we observed in Kdm6a expression in brain sub-regions make this gene an attractive candidate for a role in differential gene regulation. Furthermore, KDM6A mutations and deletions have been identified in Kabuki syndrome patients characterized by multiple anomalies including mild to severe intellectual disability, suggesting that KDM6A plays an important role in normal development. To investigate the role of KDM6A in the sex-specific control of gene expression I will focus on early neuronal differentiation using male and female ES cells derived from a novel mouse model I have recently constructed to assay allele-specific gene expression and chromatin structure. Changes in ES cells depleted of KDM6A will be monitored during neuronal differentiation to measure the effects of KDM6A depletion on neuron morphology and on the establishment and/or maintenance of chromatin marks. In addition, I will establish profiles of KDM6A occupancy in ES cells, and their neuronal derivatives. Measurements of gene expression in male and female cells will be done to look for sex-specific differences that may result from the higher levels of KDM6A in females versus males. This study represents a new avenue of research into molecular mechanisms of sexual dimorphisms. It will help to appreciate the role of histone demethylation in neurological gene regulation and will help clarify the function of KDM6A in eliciting sexual dimorphisms for the regulation of gene expression in neuronal cell differentiation and development.

Public Health Relevance

Genes that escape X inactivation such as Kdm6a are attractive candidates for a role in sex-specific gene expression in the brain because it is more highly expressed in females and encodes a powerful modifier of epigenetic marks directly associated with changes in gene expression. My proposal aims to elucidate the role of such an important epigenetic factor in the control of gene expression during neuronal differentiation, therefore contributing to a better understanding of the underlying causes of abnormal brain development in males and females.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
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Molecular Neurogenetics Study Section (MNG)
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Beckel-Mitchener, Andrea C
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University of Washington
Schools of Medicine
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Keown, Christopher L; Berletch, Joel B; Castanon, Rosa et al. (2017) Allele-specific non-CG DNA methylation marks domains of active chromatin in female mouse brain. Proc Natl Acad Sci U S A 114:E2882-E2890
Disteche, Christine M; Berletch, Joel B (2015) X-chromosome inactivation and escape. J Genet 94:591-9