Epigenetic alterations of TA-keratinocytes as underlying cause of hyperproliferation in psoriasis
Final Report Abstract
Psoriasis is a chronic inflammatory skin disease that is associated with metabolic and cardiovascular changes in addition to the skin symptoms. It is therefore considered a complex, multifactorial systemic disease that greatly reduces the quality of life of affected patients. The cutaneous inflammatory response in psoriasis is associated with reduced terminal differentiation and massively increased proliferation of epidermal keratinocytes. A possible involvement of epigenetics in psoriasis pathogenesis is suggested, but previous data were limited in their significance due to a lack of cell specificity. The aim of this study was therefore to expand our knowledge of the epigenetic alterations underlying hyperproliferation in psoriasis. The methodology used for methylome analysis was established with regard to limited sample quantities, high cell specificity and preselection in terms of functional orientation of the cells. Indeed, characterization of the methylation profile of TAC keratinocytes, which represent the proliferative keratinocyte subtype within the epidermal keratinocyte fraction, revealed that psoriatic TAC exhibit profound alterations in the methylation pattern compared to TAC from healthy donors. Surprisingly, despite the inconspicuous macroscopic appearance of non-lesional psoriatic skin, non-lesional TAC nonetheless showed signs of molecular alterations compared with healthy skin TAC. The dominance of hypermethylated DMG identified in lesional psoriatic TAC together with the dysregulation of methylation regulators could contribute to the maintenance of methylome alterations in psoriasis. Interestingly, the identified genes regulated at the mRNA-level showed little overlap with methylation changes in the corresponding genes of non-lesional TAC. In contrast, the number of DEG identified in TACs from active psoriatic lesions was significantly higher and more frequently associated with methylation changes of corresponding genes. Based on these data, we were identified GPR15L as a potential regulator of hyperproliferation in psoriasis based on its proliferation-enhancing capacity and could show that its expression was enhanced by interaction of the psoriasis-associated cytokines IL-17A, IL-22, TNFα and IL-36α in keratinocytes. In line with these data, in silico analyses suggested a transcriptional regulation of GPR15L via MAP-kinase, NF-κB and JAK/STAT signaling pathways and suggest a relevance of promoter-associated methylation changes in GPR15L regulation. In summary, these data show that profound alterations at the cellular and epigenetic level characterize psoriatic TAC keratinocytes. The altered stage-specific epigenetic identity of psoriatic TAC suggests that epigenetic regulation is already a key feature of non-lesional psoriatic skin areas. Furthermore, these data suggest a contribution of epigenetic changes to lesion predisposition in non-lesional psoriatic skin.
Publications
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Increased presence and differential molecular imprinting of transit amplifying cells in psoriasis. Journal of Molecular Medicine, 98(1), 111-122.
Witte, Katrin; Jürchott, Karsten; Christou, Demetrios; Hecht, Jochen; Salinas, Gabriela; Krüger, Ulrike; Klein, Oliver; Kokolakis, Georgios; Witte-Händel, Ellen; Mössner, Rotraut; Volk, Hans-Dieter; Wolk, Kerstin & Sabat, Robert
