Identification of the regulatory circuit governing corneal epithelial fate determination and disease trackhub data
Creators
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Smits, Jos Gerardus Adrianus1
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Lima Cunha, Dulce1
- Amini, Maryam2
- Bertolin, Marina3
- Laberthonnière, Camille4
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Qu, Jieqiong5
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Owen, Nicholas6
- Latta, Lorenz7
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Seitz, Berthold7
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Roux, Lauriane N8
- Stachon, Tanja2
- Ferrari, Stefano3
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Moosajee, Mariya6
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Aberdam, Daniel8
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Szentmary, Nora2
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van Heeringen, Simon J.4
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Zhou, Huiqing4
- 1. Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands
- 2. Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Aniridia Research, Saarland University, Homburg/Saar, Germany
- 3. Fondazione Banca degli Occhi del Veneto, Venice, Italy
- 4. Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands,
- 5. Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
- 6. Development, Ageing and Disease, UCL Institute of Ophthalmology, London, United Kingdom
- 7. Department of Ophthalmology, Saarland University Medical Center, UKS, Homburg/Saar, Germany
- 8. INSERM U976, Paris, France
Description
The transparent corneal epithelium in the eye is maintained through the homeostasis regulated by limbal stem cells, while the non-transparent 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 limbal stem cells 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 that define specific cell fates, and established their regulatory hierarchy. Single-cell RNA-seq analyses of the cornea and the epidermis confirmed these shared and cell type-specific transcription factors. Notably, the shared and limbal stem cell-specific transcription factors 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 limbal stem cell fate and its association with corneal opacity.
Files present are within the UCSC trackhub format containing bigwig and bignarrowpeak files associated with the publication:
Multi-omics analyses identify transcription factor interplay in corneal epithelial fate determination and disease
doi: https://doi.org/10.1101/2022.07.13.499857