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Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epiderm...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2023-12, Vol.120 (49), p.e2315096120-e2315096120
Main Authors: Jin, Lin, Chen, Yunjia, Muzaffar, Suhail, Li, Chao, Mier-Aguilar, Carlos A, Khan, Jasim, Kashyap, Mahendra P, Liu, Shanrun, Srivastava, Ritesh, Deshane, Jessy S, Townes, Tim M, Elewski, Boni E, Elmets, Craig A, Crossman, David K, Raman, Chander, Athar, Mohammad
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container_title Proceedings of the National Academy of Sciences - PNAS
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creator Jin, Lin
Chen, Yunjia
Muzaffar, Suhail
Li, Chao
Mier-Aguilar, Carlos A
Khan, Jasim
Kashyap, Mahendra P
Liu, Shanrun
Srivastava, Ritesh
Deshane, Jessy S
Townes, Tim M
Elewski, Boni E
Elmets, Craig A
Crossman, David K
Raman, Chander
Athar, Mohammad
description Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by / / and family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49f cells. The disruption of the enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.
doi_str_mv 10.1073/pnas.2315096120
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Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by / / and family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49f cells. The disruption of the enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. 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identifier ISSN: 0027-8424
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subjects Biological Sciences
Cell adhesion
Cell cycle
Cell differentiation
Cells (biology)
Chemokines
Chromatin - metabolism
Chromatin remodeling
CRISPR
Differentiation (biology)
DNA damage
DNA repair
Enhancers
Epigenesis, Genetic
Epigenetics
Epigenomics
Epithelial cells
Epithelium
Hidradenitis Suppurativa - genetics
Humans
Immune system
Interferon regulatory factor 3
Keratinocytes
Pathogenesis
Progenitor cells
Signatures
Skin - metabolism
Skin diseases
Stem Cells - metabolism
Transcription factors
title Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa
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