Large-scale functional inference for skin-expressing lncRNAs using expression and sequence information

JCI Insight, vol. 8

Abstract

Long noncoding RNAs (lncRNAs) regulate the expression of protein-coding genes and have been shown to play important roles in inflammatory skin diseases. However, we still have limited understanding of the functional impact of lncRNAs in skin, partly due to their tissue specificity and lower expression levels compared with protein-coding genes. We compiled a comprehensive list of 18,517 lncRNAs from different sources and studied their expression profiles in 834 RNA-Seq samples from multiple inflammatory skin conditions and cytokine-stimulated keratinocytes. Applying a balanced random forest to predict involvement in biological functions, we achieved a median AUROC of 0.79 in 10-fold cross-validation, identifying significant DNA binding domains (DBDs) for 39 lncRNAs. G18244, a skin-expressing lncRNA predicted for IL-4/IL-13 signaling in keratinocytes, was highly correlated in expression with F13A1, a protein-coding gene involved in macrophage regulation, and we further identified a significant DBD in F13A1 for G18244. Reflecting clinical implications, AC090198.1 (predicted for IL-17 pathway) and AC005332.6 (predicted for IFN-γ pathway) had significant negative correlation with the SCORAD metric for atopic dermatitis. We also utilized single-cell RNA and spatial sequencing data to validate cell type specificity. Our research demonstrates lncRNAs have important immunological roles and can help prioritize their impact on inflammatory skin diseases.

Authors 16

1. Matthew T. Patrick

   University of Michigan · Michigan Medicine

   Affiliation as printed

   Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

2. Sutharzan Sreeskandarajan

   Cincinnati Children's Hospital Medical Center · University of Michigan · Michigan Medicine

   Affiliation as printed

   Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA

   Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

   Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

3. Alanna Shefler

   University of Michigan · Michigan Medicine

   Affiliation as printed

   Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

4. Rachael Wasikowski

   University of Michigan · Michigan Medicine

   Affiliation as printed

   Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

5. Mrinal K. Sarkar

   University of Michigan · Michigan Medicine

   Affiliation as printed

   Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

6. Jiahan Chen

   North Carolina State University · University of Michigan · Michigan Medicine

   Affiliation as printed

   College of Sciences, North Carolina State University, Raleigh, North Carolina, USA

   Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

7. Tingting Qin
   Affiliation as printed

   Department of Computational Medicine & Bioinformatics and

8. Allison C. Billi

   University of Michigan · Michigan Medicine

   Affiliation as printed

   Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

9. Joanne Michelle Kahlenberg

   University of Michigan · Michigan Medicine

   Affiliation as printed

   Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

   Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA

10. Errol Prospero Prens

    Erasmus MC

    Affiliation as printed

    Department of Dermatology, Erasmus University Medical Center, Rotterdam, Netherlands

11. Alain Hovnanian

    Institut des Maladies Génétiques Imagine

    Affiliation as printed

    Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France

12. Stephan Weidinger

    University Hospital Schleswig-Holstein

    Affiliation as printed

    Department of Dermatology and Allergy, University Medical Center Schleswig-Holstein, Kiel, Germany

13. James T. Elder

    University of Michigan · Michigan Medicine · Ann Arbor VA Medical Center

    Affiliation as printed

    Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA

    Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

14. Chao‐Chung Kuo Aachen Institute for Computational Genomics Joint Research Centre for Computational Biomedicine (JRC-COMBINE)

    RWTH Aachen University

    Affiliation as printed

    Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany

15. Johann Eli Gudjonsson

    University of Michigan · Michigan Medicine

    Affiliation as printed

    Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA

16. Lam C. Tsoi

    University of Michigan · Michigan Medicine

    Affiliation as printed

    Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA

    Department of Computational Medicine & Bioinformatics and

    Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA