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Allele-Specific Gene Regulation by Kdm6a

53 Pages Posted: 3 Mar 2019 Last revised: 31 May 2019 Publication Status: Review Complete

See all articles by Joel Berletch

Joel Berletch

University of Washington, School of Medicine, Department of Pathology

Wenxiu Ma

University of Washington - Department of Genome Sciences

He Fang

University of Washington, School of Medicine, Department of Pathology

Galina N. Filippova

University of Washington, School of Medicine, Department of Pathology

Nicolas Pease

University of Washington - Department of Genome Sciences

Christine M. Disteche

University of Washington, School of Medicine, Department of Pathology

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Abstract

KDM6A demethylates the repressive histone mark H3K27me3 and thus plays an important role in developmental gene regulation. KDM6A level is female-biased due to escape from X inactivation, suggesting that this protein may play a role in sex differences. Here, we report that maternal and paternal alleles of a subset of mouse genes are differentially regulated by KDM6A. Knockouts of KDM6A in male and female embryonic stem cells derived from F1 hybrid mice result in preferential downregulation of maternal alleles of a number of genes implicated in development, whereas upregulated genes show no allelic preference. A subset of maternally expressed imprinted genes expressed in ovary or placenta –the Meg3-Rian cluster, Xlr cluster and Phlda2- are dependent on KDM6A for expression. Downregulated maternal but not paternal alleles demonstrate a loss of chromatin accessibility, but without the expected changes in H3K27me3 levels, which increase only on downregulated paternal alleles. These results illustrate parent-of-origin mechanisms of gene regulation by KDM6A, consistent with both histone demethylation-dependent and -independent effects.

Suggested Citation

Berletch, Joel and Ma, Wenxiu and Fang, He and Filippova, Galina N. and Pease, Nicolas and Disteche, Christine M., Allele-Specific Gene Regulation by Kdm6a. Available at SSRN: https://ssrn.com/abstract=3345548 or http://dx.doi.org/10.2139/ssrn.3345548
This version of the paper has not been formally peer reviewed.

Joel Berletch (Contact Author)

University of Washington, School of Medicine, Department of Pathology ( email )

Seattle, WA 98115
United States

Wenxiu Ma

University of Washington - Department of Genome Sciences ( email )

Seattle, WA 98195
United States

He Fang

University of Washington, School of Medicine, Department of Pathology

Seattle, WA 98115
United States

Galina N. Filippova

University of Washington, School of Medicine, Department of Pathology

Seattle, WA 98115
United States

Nicolas Pease

University of Washington - Department of Genome Sciences

Seattle, WA 98195
United States

Christine M. Disteche

University of Washington, School of Medicine, Department of Pathology ( email )

Seattle, WA 98115
United States

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