Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis

Mingsen Li, Huaxing Huang, Lingyu Li, Chenxi He, Liqiong Zhu, Huizhen Guo, Li Wang, Jiafeng Liu, Siqi Wu, Jingxin Liu, Tao Xu, Zhen Mao, Nan Cao, Kang Zhang, Fei Lan, Junjun Ding, Jin Yuan, Yizhi Liu () and Hong Ouyang ()
Additional contact information
Mingsen Li: Sun Yat-sen University
Huaxing Huang: Sun Yat-sen University
Lingyu Li: Sun Yat-sen University
Chenxi He: Fudan University
Liqiong Zhu: Sun Yat-sen University
Huizhen Guo: Sun Yat-sen University
Li Wang: Sun Yat-sen University
Jiafeng Liu: Sun Yat-sen University
Siqi Wu: Sun Yat-sen University
Jingxin Liu: Sun Yat-Sen University
Tao Xu: Sun Yat-Sen University
Zhen Mao: Sun Yat-sen University
Nan Cao: Sun Yat-Sen University
Kang Zhang: Sun Yat-sen University
Fei Lan: Fudan University
Junjun Ding: Sun Yat-Sen University
Jin Yuan: Sun Yat-sen University
Yizhi Liu: Sun Yat-sen University
Hong Ouyang: Sun Yat-sen University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20713-z

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DOI: 10.1038/s41467-020-20713-z

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