Core transcription regulatory circuitry orchestrates corneal epithelial homeostasis

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.

dsRNA Induced IFNβ-MMP13 Axis Drives Corneal Wound Healing

“… 6 , 35 Proper wound repair is vital for corneal epithelial integrity and transparency. 36 , 37 Our work provides new insights into the corneal wound healing process and identifies the IFNβ-MMP13 axis as a potential therapeutic target to promote corneal regeneration.…”

Chromatin binding of survivin regulates glucose metabolism in the IFN-γ producing CD4+T cells

“…On the functional level, the effects of IRF1 and SMAD3 have been mostly studied through binding to the promoter regions of non-identical genes that often regulate opposing transcriptional programs (58,59). IRF1 and SMAD3 were identified among the TFs binding to the distant regulatory regions and facilitating chromatin accessibility for other proteins (60,61). SMAD3 has been attributed chromatin remodelling properties by coordination of super-enhancers (62)(63)(64).…”

Chromatin bound by survivin regulates the glycolytic switch in interferon-γ producing CD4+ T cells

“…JUN did not interact with survivin in western blot and was not enriched in the survivin peaks in open chromatin; but neither of those ndings exclude the possibility of an interaction between AP-1 TFs and SMAD3 40 or their consolidating effect on the IRF1/survivin/SMAD3 complex. Conversely, SMAD3/4 and AP1 proteins are frequently found on distant cis-regulatory regions, where they facilitate promoter-enhancer interactions through chromatin looping and triggering transcription 41 . Cell activation with TGFb elicits a widespread SMAD-dependent increase in chromatin accessibility 62 .…”