Retinoic acid and BMP4 cooperate with p63 to alter chromatin dynamics during surface epithelial commitment. (December 2018)

• Record Type: Journal Article
• Authors: Pattison, Jillian; Melo, Sandra; Piekos, Samantha; Torkelson, Jessica; Bashkirova, Elizaveta; Mumbach, Maxwell; Rajasingh, Charlotte; Zhen, Hanson; Li, Lingjie; Liaw, Eric; Alber, Daniel; Rubin, Adam; Shankar, Gautam; Bao, Xiaomin; Chang, Howard; Khavari, Paul; Oro, Anthony
• Is Part Of: Nature genetics. Volume 50:Number 12(2018)
• Page Start: 1658
• Page End: 1665
• Publication Date: 2018-12
• Subjects: Human genetics -- Periodicals; 576.505
• DOI: 10.1038/s41588-018-0263-0
• Languages: English
• ISSNs: 1061-4036

Abstract

Abstract Human embryonic stem cell (hESC) differentiation promises advances in regenerative medicine1–3, yet conversion of hESCs into transplantable cells or tissues remains poorly understood. Using our keratinocyte differentiation system, we employ a multi-dimensional genomics approach to interrogate the contributions of inductive morphogens retinoic acid and bone morphogenetic protein 4 (BMP4) and the epidermal master regulator p63 (encoded byTP63 )4, 5 during surface ectoderm commitment. In contrast to other master regulators6–9, p63 effects major transcriptional changes only after morphogens alter chromatin accessibility, establishing an epigenetic landscape for p63 to modify. p63 distally closes chromatin accessibility and promotes accumulation of H3K27me3 (trimethylated histone H3 lysine 27). Cohesin HiChIP10 visualizations of chromosome conformation show that p63 and the morphogens contribute to dynamic long-range chromatin interactions, as illustrated byTFAP2C regulation11 . Our study demonstrates the unexpected dependency of p63 on morphogenetic signaling and provides novel insights into how a master regulator can specify diverse transcriptional programs based on the chromatin landscape induced by exposure to specific morphogens. Retinoic acid and BMP4 signaling, together with p63, contribute to dynamic long-range chromatin interactions during keratinocyte differentiation. TP63 decreases chromatin accessibility and promotes H3K27me3 accumulation at enhancers.