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Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis

Author

Listed:
  • 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
    Macau University of Science and Technology)

  • Fei Lan

    (Fudan University)

  • Junjun Ding

    (Sun Yat-Sen University)

  • Jin Yuan

    (Sun Yat-sen University)

  • Yizhi Liu

    (Sun Yat-sen University
    Chinese Academy of Medical Sciences)

  • Hong Ouyang

    (Sun Yat-sen University)

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.

Suggested Citation

  • 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 , 2021. "Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20713-z
    DOI: 10.1038/s41467-020-20713-z
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    Cited by:

    1. Mingsen Li & Huizhen Guo & Bofeng Wang & Zhuo Han & Siqi Wu & Jiafeng Liu & Huaxing Huang & Jin Zhu & Fengjiao An & Zesong Lin & Kunlun Mo & Jieying Tan & Chunqiao Liu & Li Wang & Xin Deng & Guigang L, 2024. "The single-cell transcriptomic atlas and RORA-mediated 3D epigenomic remodeling in driving corneal epithelial differentiation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Mingsen Li & Huaxing Huang & Bofeng Wang & Shaoshuai Jiang & Huizhen Guo & Liqiong Zhu & Siqi Wu & Jiafeng Liu & Li Wang & Xihong Lan & Wang Zhang & Jin Zhu & Fuxi Li & Jieying Tan & Zhen Mao & Chunqi, 2022. "Comprehensive 3D epigenomic maps define limbal stem/progenitor cell function and identity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Mijeong Kim & Yu Jin Jang & Muyoung Lee & Qingqing Guo & Albert J. Son & Nikita A. Kakkad & Abigail B. Roland & Bum-Kyu Lee & Jonghwan Kim, 2024. "The transcriptional regulatory network modulating human trophoblast stem cells to extravillous trophoblast differentiation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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