288 ATAC-Seq analysis reveals a widespread increase of chromatin accessibility in psoriasis

Psoriasis is a common skin disease characterized by hyperproliferative keratinocytes and turbulent immune response, the exact aetiology remains essentially unknown. Genetic, epigenetic and several transcription factors have been implicated in the modulation of chromatin accessibilities. To better understand underlying regulatory network for psoriasis, we performed comparative analysis of chromatin accessibility in 19 psoriatic (PP), 15 non-psoriatic (PN) and 21 normal (NN) skin tissues via ATAC-seq. More than 40% of ATAC-seq peaks in our dataset overlap the open regions of primary keratinocyte cells and skin tissues from the ENCODE project. We identified 4,915 significantly differential peaks shared in both PP vs. PN and PP vs NN comparisons, nearly all of which are predominately more accessible in psoriatic skin tissues. The psoriasis-associated accessible peaks are highly enriched in hypomethylated regions and negatively correlated with expression of proximate genes, suggesting DNA methylation might play roles in modulating accessibility in psoriasis. Our data also indicated disease susceptibility variations might act as active regulatory elements and modulate gene expression. FRA1/AP-1 was identified as a key transcription factor in modulating expression of psoriasis-associated genes.Immunohistochemistry and immuunofluoresence analysis showed upregulated FOSL1 expression appeared in both basal and suprabasal epidermal skins, with more pronounced significance in suprabasal layer.To better understand molecular changes underlying these biological processes, we firstly overexpressed FRA1 in normal human epidermal keratinocytes (NHEKs) and performed RNA-seq analysis. The highly differentially expressed genes included CXCL1, IL23A, TNFAIP3, NFKB1, NFKBIB and IL17D, most of them previously implicated in immune disturbance for Ps.These findings revealed that global increases in chromatin accessibility may play a critical role in the development and progression of psoriasis.