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Peer-reviewedCC BY-NCScience Advances

FOSL1-associated condensates modulate superenhancer-mediated selected IL-1 family gene activation in psoriasis

  • Yueqi Qiu1,2,3
  • Ke Sun1,2
  • Yaqin Yu2,4
  • Huihui Hou2,5
  • Ruifang Wu4
  • Qianjin Lu1,2,3,4
  • Ming Zhao1,2,3,4
5 affiliations
  1. 1Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
  2. 2Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China.
  3. 3Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Nanjing, China.
  4. 4Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, Changsha, China.
  5. 5School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.
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Abstract

Psoriasis is a chronic inflammatory skin disease involving abnormal keratinocyte gene expression, yet the upstream epigenetic mechanisms driving these alterations remain unclear. Here we performed multiomics analyses (chromatin immunoprecipitation sequencing, CUT&Tag, ATAC-seq, and RNA sequencing) on psoriatic lesions, perilesional skin, healthy skin, and M5-stimulated HaCaT cells. Functional validation was performed using CRISPR-mediated superenhancer (SE) editing, epigenetic modulation, circular chromosome conformation capture sequencing, assay for chromatin-bound condensates by exploratory sequencing, coimmunoprecipitation, and fluorescence recovery after photobleaching. We found widespread activation of enhancers and SEs in lesions, including an interleukin 1 (IL-1)-SE regulating IL1A, IL1B, and IL36G transcription. BET inhibition reduced SE activity, repressed IL-1 cytokines, and relieved psoriasis-like inflammation in vivo. Fos-like antigen 1 (FOSL1) was identified as a key transcription factor enriched in active SEs and associated with condensate formation, contributing to the maintenance of EP300 occupancy and histone H3 lysine 27 acetylation deposition. Macrophage-derived IL-1 up-regulated FOSL1 through mitogen-activated protein kinase/ERK signaling, forming a positive feedback loop that amplified inflammation. This study revealed an FOSL1-SE-centered regulatory network driving keratinocyte inflammatory responses, providing previously unknown therapeutic targets for psoriasis.

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Cite

BibTeXRIS
BibTeX
@article{qiu2026fosl1associated,
  title = {{FOSL1-associated condensates modulate superenhancer-mediated selected IL-1 family gene activation in psoriasis}},
  author = {Yueqi Qiu and Ke Sun and Yaqin Yu and Huihui Hou and Ruifang Wu and Qianjin Lu and Ming Zhao},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeh6541},
  url = {https://www.science.org/doi/abs/10.1126/sciadv.aeh6541},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - FOSL1-associated condensates modulate superenhancer-mediated selected IL-1 family gene activation in psoriasis
AU  - Yueqi Qiu
AU  - Ke Sun
AU  - Yaqin Yu
AU  - Huihui Hou
AU  - Ruifang Wu
AU  - Qianjin Lu
AU  - Ming Zhao
PY  - 2026
DA  - 2026/10/28
JO  - Science Advances
DO  - 10.1126/sciadv.aeh6541
UR  - https://www.science.org/doi/abs/10.1126/sciadv.aeh6541
AB  - Psoriasis is a chronic inflammatory skin disease involving abnormal keratinocyte gene expression, yet the upstream epigenetic mechanisms driving these alterations remain unclear. Here we performed multiomics analyses (chromatin immunoprecipitation sequencing, CUT&Tag, ATAC-seq, and RNA sequencing) on psoriatic lesions, perilesional skin, healthy skin, and M5-stimulated HaCaT cells. Functional validation was performed using CRISPR-mediated superenhancer (SE) editing, epigenetic modulation, circular chromosome conformation capture sequencing, assay for chromatin-bound condensates by exploratory sequencing, coimmunoprecipitation, and fluorescence recovery after photobleaching. We found widespread activation of enhancers and SEs in lesions, including an interleukin 1 (IL-1)-SE regulating IL1A, IL1B, and IL36G transcription. BET inhibition reduced SE activity, repressed IL-1 cytokines, and relieved psoriasis-like inflammation in vivo. Fos-like antigen 1 (FOSL1) was identified as a key transcription factor enriched in active SEs and associated with condensate formation, contributing to the maintenance of EP300 occupancy and histone H3 lysine 27 acetylation deposition. Macrophage-derived IL-1 up-regulated FOSL1 through mitogen-activated protein kinase/ERK signaling, forming a positive feedback loop that amplified inflammation. This study revealed an FOSL1-SE-centered regulatory network driving keratinocyte inflammatory responses, providing previously unknown therapeutic targets for psoriasis.
SN  - 2375-2548
ER  -