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H2A.J is a driver of IL-17-associated inflammation in Th17 cells and keratinocytes [Th17 cells]

ABSTRACT: Psoriasis is a common autoinflammatory disease driven by excessive IL-17 expression. While the pathomechanism of the disease has been revealed, epigenetic factors contributing to psoriasis are less well understood. Here, we investigated the role of the rather unknown histone variant H2A.J in psoriasis. We uncovered that H2A.J becomes overexpressed in the skin of psoriasis patients. Furthermore, global H2A.J KO mice are partially protected against experimentally induced psoriasis, shown by reduced immune cell infiltration and lower hyperkeratosis of the skin. This was likely due to the diminished expression of various chemokines and cytokines in the skin of psoriatic H2A.J KO mice, including CXCL1, CCL3, or IL-17A. Further analysis revealed that H2A.J regulated a subset of IL-17-responsive genes and differentiation markers in keratinocytes, thereby partially explaining the observed phenotype in the IMQ-treated H2A.J KO mice. Furthermore, we uncovered a T-cell intrinsic function of H2A.J, as it specifically mediated the expression of several effector molecules such as Il17a in TH17 cells, leading to reduced levels of functional TH17 cells in IMQ-treated H2A.J KO mice. Thus, we identified H2A.J as a key epigenetic regulator of IL-17-associated inflammation, which controls the (chronic) activation of TH17 cells and keratinocytes in psoriasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE307885 | GEO | 2026/09/21

REPOSITORIES: GEO

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Project description:This dataset contains quantitative, bottom-up DIA proteomics data generated as part of a larger study entitled "AI-Guided CRISPR Screen Reveals Repurposed Drugs as Topical Psoriasis Therapeutics," and is organized into two complementary sub-studies.Sub-study 1 – Pharmacological Rescue in a Mouse Psoriasis ModelThe first proteomics component was designed to molecularly characterize pharmacological rescue effects in an imiquimod (IMQ)-induced mouse psoriasis model following prioritization of candidate targets from a CRISPR-based genetic screen. Mouse skin samples were collected from five experimental conditions: untreated control, IMQ only, IMQ plus the ALOX5 inhibitor zileuton, IMQ plus the OXTR antagonist cligosiban, and IMQ plus an IL-17RA blocking antibody serving as a positive control. Skin tissues were processed for bottom-up proteomics and analyzed using dia-PASEF on a timsTOF Ultra 2 mass spectrometer coupled to an Evosep One liquid chromatography system. Proteomic data were analyzed using DIA-NN in library-free mode against a SwissProt-reviewed Mus musculus reference proteome (Mouse_SwissProt_CanonicalAndIsoform_20250324.fasta). The resulting protein-level quantitative dataset enables assessment of molecular pathways associated with IMQ-driven inflammation and the extent to which these signatures are modulated or rescued by pharmacological intervention.Sub-study 2 – CRISPR Knockout Proteomics in Human KeratinocytesThe second proteomics component was designed to characterize the proteomic consequences of genetically ablating the candidate therapeutic targets ALOX5 and OXTR in a human cellular psoriasis-relevant context. Human keratinocytes were subjected to CRISPR-mediated knockout of either ALOX5 or OXTR and compared against wild-type controls. Samples were processed for bottom-up proteomics and analyzed using dia-PASEF on a timsTOF Ultra 2 mass spectrometer coupled to an Evosep One liquid chromatography system. Proteomic data were analyzed using DIA-NN in library-free mode against a SwissProt-reviewed Homo sapiens reference proteome. The resulting dataset enables assessment of the downstream molecular signatures driven by loss of each target in human keratinocytes.

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H2A.J is a driver of IL-17-associated inflammation in Th17 cells and keratinocytes [Th17 cells]

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