Lineage Commitment of Dermal Fibroblast Progenitors is Mediated by Chromatin De-repression

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the mechanisms that regulate lineage commitment of naive dermal progenitors to form niches around the hair follicle, dermis, and hypodermis, are unknown. In our study, we used multimodal single-cell approaches, epigenetic assays, and allografting techniques to define a DFP state and the mechanisms that govern its differentiation potential. Our results indicate that the overall chromatin profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage specific genes. Surprisingly, the repressed chromatin profile of DFPs renders them unable to reform skin in allograft assays despite their multipotent potential. Distinct fibroblast lineages, such as the dermal papilla and adipocytes contained specific chromatin profiles that were de-repressed during late embryogenesis by the H3K27-me3 demethylase, Kdm6b/Jmjd3. Tissue-specific deletion of Kdm6b/Jmjd3 resulted in ablating the adipocyte compartment and inhibiting mature dermal papilla functions in single-cell-RNA-seq, ChIPseq, and allografting assays. Altogether our studies reveal a mechanistic multimodal understanding of how DFPs differentiate into distinct fibroblast lineages, and we provide a novel multiomic search-tool within skinregeneration.org.

Authors 8

1. Quan M Phan

   Washington State University

   Affiliation as printed

   School of Molecular Biosciences, Washington State University, Pullman, WA

   School of Molecular Biosciences, Washington State University

2. Lucia Salz Aachen

   RWTH Aachen University

   Affiliation as printed

   North Rhine-Westphalia Technical University of Aachen, Aachen, Germany

   North Rhine-Westphalia Technical University of Aachen

3. Sam S Kindl

   Washington State University

   Affiliation as printed

   School of Molecular Biosciences, Washington State University, Pullman, WA

   School of Molecular Biosciences, Washington State University

4. Jayden S Lopez

   Washington State University

   Affiliation as printed

   School of Molecular Biosciences, Washington State University, Pullman, WA

   School of Molecular Biosciences, Washington State University

5. Sean M. Thompson

   Washington State University

   Affiliation as printed

   School of Molecular Biosciences, Washington State University, Pullman, WA

   School of Molecular Biosciences, Washington State University

6. Jasson Makkar

   Washington State University

   Affiliation as printed

   School of Molecular Biosciences, Washington State University, Pullman, WA

   School of Molecular Biosciences, Washington State University

7. Iwona M. Driskell

   Washington State University

   Affiliation as printed

   School of Molecular Biosciences, Washington State University, Pullman, WA

   School of Molecular Biosciences, Washington State University

8. Ryan R. Driskell corresponding

   Washington State University

   Affiliation as printed

   Center for Reproductive Biology, Washington State University, Pullman, WA

   School of Molecular Biosciences, Washington State University, Pullman, WA

   Center for Reproductive Biology, Washington State University

   School of Molecular Biosciences, Washington State University