UTX/KDM6A suppresses AP-1 and a gliogenesis program during neural differentiation of human pluripotent stem cells
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Epigenetics & Chromatin Open Access
RESEARCH
UTX/KDM6A suppresses AP‑1 and a gliogenesis program during neural differentiation of human pluripotent stem cells Beisi Xu1†, Brett Mulvey2†, Muneeb Salie2, Xiaoyang Yang2, Yurika Matsui2, Anjana Nityanandam2, Yiping Fan1 and Jamy C. Peng2*
Abstract Background: UTX/KDM6A is known to interact and influence multiple different chromatin modifiers to promote an open chromatin environment to facilitate gene activation, but its molecular activities in developmental gene regulation remain unclear. Results: We report that in human neural stem cells, UTX binding correlates with both promotion and suppression of gene expression. These activities enable UTX to modulate neural stem cell self-renewal, promote neurogenesis, and suppress gliogenesis. In neural stem cells, UTX has a less influence over histone H3 lysine 27 and lysine 4 methylation but more predominantly affects histone H3 lysine 27 acetylation and chromatin accessibility. Furthermore, UTX suppresses components of AP-1 and, in turn, a gliogenesis program. Conclusions: Our findings revealed that UTX coordinates dualistic gene regulation to govern neural stem cell properties and neurogenesis–gliogenesis switch. Background The chromatin modifier UTX/KDM6A has a crucial influence on normal development and disease. In mice, the loss of UTX leads to embryonic lethality concurrent with brain and heart malformations [1, 2]. In humans, UTX mutations are causally linked to developmental disorders such as Kabuki syndrome and Group 4 pediatric medulloblastoma [3–5]. Recurrent UTX mutations occur in 14 pediatric cancer types and 13 adult cancer types [6– 9], suggesting that UTX dysfunction broadly promotes cancer progression. UTX was originally discovered as a demethylase of histone H3-methylated-lysine 27 (H3K27me) [10–14], *Correspondence: [email protected] † Beisi Xu and Brett Mulvey contributed equally to this work. 2 Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA Full list of author information is available at the end of the article
and has since been shown to interact with and affect the activities of H3K27 acetyltransferase P300 [15], H3K4 methyltransferases [11, 16], and the chromatin remodeler SWI/SNF [17, 18]. By removing suppressive chromatin modifications and promoting open chromatin structure, UTX presumably facilitates the activation of key developmental regulators. In mouse embryonic stem cells (ESCs), Utx mediates enhancer activation [15] and recruitment of transcription factors to chromatin [19]. Furthermore, in mice, Utx enhances the induction of pluripotency in mature fibroblasts [20]. However, the activities and influence of UTX genome wide in a developmental context remain unclear. Whether UTX facilitates gene activation only and whether it influences gene expression only through chromatin-modifying activities are also unknown. These gaps hinder the understanding of epigenetic influence over normal and diseased development as well as the etiology
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