Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis.
Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis.
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核心转录调节电路协调角膜上皮稳态
DOI：
10.1038/s41467-020-20713-z
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发表时间：
2021-01-18
影响因子：
16.6
通讯作者：
Ouyang H
中科院分区：
文献类型：
--
作者：
Li M;Huang H;Li L;He C;Zhu L;Guo H;Wang L;Liu J;Wu S;Liu J;Xu T;Mao Z;Cao N;Zhang K;Lan F;Ding J;Yuan J;Liu Y;Ouyang H
成体干细胞的特性、可塑性和动态平衡精确地由谱系限制的表观遗传和转录调控网络来协调。在这里，通过整合超级增强子和染色质可及性景观，我们描绘了角膜缘干细胞(LSCs)的核心转录调节电路(CRC)，发现RUNX1和Smad3是维持角膜上皮特性和自身稳定所必需的。RUNX1或Smad3耗竭抑制剂PAX6并诱导LSCs分化为表皮样上皮细胞。RUNX1、PAX6和SMAD3(RP)相互作用，协同建立CRC来管理特定血统的顺式调控图谱。此外，RUNX1通过调节H3K27ac的沉积来形成LSC染色质结构。RPS协作障碍导致细胞身份转换和角膜上皮功能障碍，这与多种人类角膜疾病密切相关。我们的工作强调了CRC TF在建立干细胞身份和谱系承诺方面的协同性，并为人类分层上皮细胞的动态平衡和发病机制提供了全面的调节原则。
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.RUNX1orSMAD3depletion inhibitsPAX6and 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-specificcis-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.
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