Journal Article

Identification of the regulatory circuit governing corneal epithelial fate determination and disease

Ferrari, Stefano, Stachon, Tanja, Moosajee, Mariya, Szentmary, Nora, Zhou, Huiqing, Latta, Lorenz, Cunha, Dulce Lima, Laberthonnière, Camille, Amini, Maryam, Qu, Jieqiong, Aberdam, Daniel, Smits, Jos G. A., Owen, Nicholas, Bertolin, Marina, Roux, Lauriane N., Seitz, Berthold, van Heeringen, Simon J.

2023

Overview

The transparent corneal epithelium in the eye is maintained through the homeostasis regulated by limbal stem cells (LSCs), while the nontransparent epidermis relies on epidermal keratinocytes for renewal. Despite their cellular similarities, the precise cell fates of these two types of epithelial stem cells, which give rise to functionally distinct epithelia, remain unknown. We performed a multi-omics analysis of human LSCs from the cornea and keratinocytes from the epidermis and characterized their molecular signatures, highlighting their similarities and differences. Through gene regulatory network analyses, we identified shared and cell type-specific transcription factors (TFs) that define specific cell fates and established their regulatory hierarchy. Single-cell RNA-seq (scRNA-seq) analyses of the cornea and the epidermis confirmed these shared and cell type-specific TFs. Notably, the shared and LSC-specific TFs can cooperatively target genes associated with corneal opacity. Importantly, we discovered that FOSL2 , a direct PAX6 target gene, is a novel candidate associated with corneal opacity, and it regulates genes implicated in corneal diseases. By characterizing molecular signatures, our study unveils the regulatory circuitry governing the LSC fate and its association with corneal opacity.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Biology and Life Sciences / Cell cycle / Cell differentiation / Cell Differentiation - genetics / Cellular control mechanisms / Circuits / Cornea / Cornea - metabolism / Corneal Opacity - metabolism / Disease / Epidermis / Epigenetics / Epithelial cells / Epithelium / Epithelium, Corneal - metabolism / Eye diseases / Gene expression / Genes / Health aspects / Homeostasis / Humans / Keratinocytes / Limbus Corneae - metabolism / Medicine and Health Sciences / Mutation / Network analysis / Opacity / Pax6 protein / Physical Sciences / Retina / Signatures / Similarity / Stem cells / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism