Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis– and psoriasis-associated genes - 05/05/21
, Rapolas Spalinskas, PhD a, Samina Asad, PhD b, Kunal Das Mahapatra, MSc b, Pontus Höjer, MSc a, Anandashankar Anil, MSc a, Jesper Eisfeldt, PhD c, d, Ankit Srivastava, PhD b, Pernilla Nikamo, PhD b, Anaya Mukherjee, MSc b, Kyu-Han Kim, PhD e, Otto Bergman, PhD f, Mona Ståhle, MD, PhD b, Enikö Sonkoly, MD, PhD b, g, h, Andor Pivarcsi, PhD b, h, i, Carl-Fredrik Wahlgren, MD, PhD b, Magnus Nordenskjöld, MD, PhD c, d, Fulya Taylan, PhD c, d, Maria Bradley, MD, PhD b, g, ∗, Isabel Tapia-Páez, PhD b, ∗Abstract |
Background |
Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear.
Objective |
We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate.
Methods |
We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies.
Results |
We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis.
Conclusions |
Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Atopic dermatitis, psoriasis, Capture Hi-C, AFG1L, CLINT1, ADO, LINC00302, RP1-140J1.1
Abbreviations used : AD, ADO, Capture Hi-C, CRISPR, DE, EDC, FDR, GWAS, H3K27Ac, Hi-C, LD, LINC, PIR, SAM, sgRNA, SNP, TF
Plan
| Supported by the Swedish Research Council (Vetenskapsrådet, grant 78081) and the Swedish Skin Foundation (grants 2544 and 2968). M.B. and I.T.P. received the Sanofi Genzyme Award for Type 2 Innovation Grant 2018 for this study. A.P. was funded by Swedish Skin Foundation (grants 2709 and 2948) and the Swedish Cancer Society (grant CAN 2018/801). The computations and data handling were made possible by resources provided by the Swedish National Infrastructure for Computing at Rackham (UPPMAX), which was partially funded by the Swedish Research Council through grant agreement 2018-05973. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 5
P. 1742-1752 - mai 2021 Retour au numéro
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