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.
Submitted Version
Published Version
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