Journal Article

Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis

Ouyang, Hong, Wang, Li, Liu, Jingxin, Li, Lingyu, Cao, Nan, Zhang, Kang, Ding, Junjun, Liu, Jiafeng, Guo, Huizhen, Li, Mingsen, He, Chenxi, Liu, Yizhi, Yuan, Jin, Xu, Tao, Mao, Zhen, Lan, Fei, Huang, Huaxing, Zhu, Liqiong, Wu, Siqi

2021

Overview

Adult stem cell identity, plasticity, and homeostasis are precisely orchestrated by lineage-restricted epigenetic and transcriptional regulatory networks. Here, by integrating super-enhancer and chromatin accessibility landscapes, we delineate core transcription regulatory circuitries (CRCs) of limbal stem/progenitor cells (LSCs) and find that RUNX1 and SMAD3 are required for maintenance of corneal epithelial identity and homeostasis. RUNX1 or SMAD3 depletion inhibits PAX6 and induces LSCs to differentiate into epidermal-like epithelial cells. RUNX1, PAX6, and SMAD3 (RPS) interact with each other and synergistically establish a CRC to govern the lineage-specific cis -regulatory atlas. Moreover, RUNX1 shapes LSC chromatin architecture via modulating H3K27ac deposition. Disturbance of RPS cooperation results in cell identity switching and dysfunction of the corneal epithelium, which is strongly linked to various human corneal diseases. Our work highlights CRC TF cooperativity for establishment of stem cell identity and lineage commitment, and provides comprehensive regulatory principles for human stratified epithelial homeostasis and pathogenesis. Corneal epithelium shares similar molecular signatures to other stratified epithelia. Here, the authors map super-enhancers and accessible chromatin in corneal epithelium, identifying a transcription regulatory circuit, including RUNX1, PAX6, and SMAD3, required for corneal epithelial identity and homeostasis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/89 / 14 / 14/1 / 38/23 / 45/15 / 45/91 / 631/208/176 / 631/337/2019 / 631/337/572 / 631/532/2118 / 631/532/2441 / Accessibility / Adolescent / Adult / Adult Stem Cells - metabolism / Aged / Cell differentiation / Cell Lineage - genetics / Cell Plasticity - genetics / Cells, Cultured / Child / Chromatin / Chromatin - metabolism / Chromatin Immunoprecipitation Sequencing / Circuits / Core Binding Factor Alpha 2 Subunit - genetics / Core Binding Factor Alpha 2 Subunit - metabolism / Cornea / Corneal Diseases - genetics / Corneal Diseases - pathology / Depletion / Enhancers / Epigenetics / Epithelial cells / Epithelium / Epithelium, Corneal - cytology / Epithelium, Corneal - physiology / Eye diseases / Female / Gene Expression Regulation / Gene Knockdown Techniques / Gene Regulatory Networks - physiology / Homeostasis / Humanities and Social Sciences / Humans / Limbus Corneae - cytology / Male / Middle Aged / multidisciplinary / Pathogenesis / Pax6 protein / PAX6 Transcription Factor - metabolism / Primary Cell Culture / Progenitor cells / RNA-Seq / Runx1 protein / Science / Science (multidisciplinary) / Smad3 protein / Smad3 Protein - genetics / Smad3 Protein - metabolism / Stem cells / Transcription