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Cell-Type-Resolved Acetylation Regulator Atlas Defines Immune Endotypes and Druggable Vulnerabilities in Psoriasis.

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Summary

This study reveals how lysine acetylation patterns in immune cells are altered in psoriasis, identifying specific epigenetic regulators and defining distinct disease endotypes for targeted therapies.

Keywords:
HDACKATdisease endotypesepigenetic therapylysine acetylationpsoriasissingle-cell RNA-seq

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Area of Science:

  • Epigenetics and Immunology
  • Dermatology and Translational Medicine

Background:

  • Psoriasis relapse post-treatment suggests persistent epigenetic alterations in lesional immune cells.
  • Lysine acetylation's role in immune cell function is crucial but not fully understood in psoriasis.
  • Cell-type-specific acetylation landscapes and their clinical relevance in psoriasis require detailed investigation.

Purpose of the Study:

  • To map the cell-type-resolved landscape of lysine acetylation regulators in psoriasis.
  • To define acetylation endotypes and their association with distinct inflammatory pathways.
  • To identify potential epigenetic therapeutic targets for stratified psoriasis treatment.

Main Methods:

  • Integration of bulk transcriptome and single-cell RNA sequencing data from human psoriatic and healthy skin.
  • Development of a diagnostic acetylation-regulator signature and unsupervised clustering for endotype definition.
  • Validation of key regulators in a mouse model and independent human datasets, employing motif enrichment and drug-target analysis.

Main Results:

  • Sixteen acetylation regulators were differentially expressed, with HDAC1 upregulated and KAT2A downregulated.
  • A 13-gene signature accurately discriminated psoriasis, identifying two distinct acetylation endotypes.
  • Single-cell analysis revealed immune-specific acetylation modules linked to IL-17 inflammatory programs.

Conclusions:

  • This study provides an integrated atlas linking acetylation regulators to specific immune cells in psoriasis.
  • Defined acetylation endotypes correlate with distinct inflammatory states, paving the way for personalized medicine.
  • Identified epigenetic targets and compounds offer a rationale for stratified therapeutic strategies in psoriasis.