Epigenome-wide DNA methylation regulates cardinal pathological features of psoriasis

Abstract

BackgroundPsoriasis is a chronic inflammatory autoimmune skin disorder. Several studies suggested psoriasis to be a complex multifactorial disease, but the exact triggering factor is yet to be determined. Evidences suggest that in addition to genetic factors, epigenetic reprogramming is also involved in psoriasis development. Major histopathological features, like increased proliferation and abnormal differentiation of keratinocytes, and immune cell infiltrations are characteristic marks of psoriatic skin lesions. Following therapy, histopathological features as well as aberrant DNA methylation reversed to normal levels. To understand the role of DNA methylation in regulating these crucial histopathologic features, we investigated the genome-wide DNA methylation profile of psoriasis patients with different histopathological features.ResultsGenome-wide DNA methylation profiling of psoriatic and adjacent normal skin tissues identified several novel differentially methylated regions associated with psoriasis. Differentially methylated CpGs were significantly enriched in several psoriasis susceptibility (PSORS) regions and epigenetically regulated the expression of key pathogenic genes, even with low-CpG promoters. Top differentially methylated genes overlapped with PSORS regions including S100A9, SELENBP1, CARD14, KAZN and PTPN22 showed inverse correlation between methylation and gene expression. We identified differentially methylated genes associated with characteristic histopathological features in psoriasis. Psoriatic skin with Munro’s microabscess, a distinctive feature in psoriasis including parakeratosis and neutrophil accumulation at the stratum corneum, was enriched with differentially methylated genes involved in neutrophil chemotaxis. Rete peg elongation and focal hypergranulosis were also associated with epigenetically regulated genes, supporting the reversible nature of these characteristic features during remission and relapse of the lesions.ConclusionOur study, for the first time, indicated the possible involvement of DNA methylation in regulating the cardinal pathophysiological features in psoriasis. Common genes involved in regulation of these pathologies may be used to develop drugs for better clinical management of psoriasis.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0541-9) contains supplementary material, which is available to authorized users.

Loss of the Epigenetic Mark 5-hmC in Psoriasis: Implications for Epidermal Stem Cell Dysregulation

“…Thus, loss of 5-hmC in psoriasis appears to function, at least in part, in modulating gene expression important for maintenance of stem cell behavior during psoriasis pathogenesis. DNA methylation profiling in psoriasis has indicated previously that hypermethylation in lesional skin with altered expression of differentially methylated genes contributes to the psoriatic phenotype (Chandra et al, 2018;Zhang et al, 2010;Zhou et al, 2016). Successful treatment of psoriasis with phototherapy not only significantly reduced the histopathological features in psoriasis, but also reverted DNA methylation to a more normal pattern (Gu et al, 2015;Ozkanli et al, 2015).…”

“…DNA methyltransferases are known to be essential in preserving the self-renewing capacity of stem cells by maintaining DNA methylation patterns (Sen et al, 2010). Genome-wide studies have established aberrant DNA methylation sites that correlate altered gene expression with major histopathological features of psoriasis (Chandra et al, 2018;Zhou et al, 2016). Furthermore, restoration to a more normal methylation status at specific loci was seen in patients who experienced improvement of their psoriasis from antietumor necrosis factor a therapy or UVB phototherapy (Gu et al, 2015;Roberson et al, 2012).…”

Environmental risk factors and epigenetic alternations in psoriasis

“…Recent studies by Chandra et al and Zhao et al report epigenome-wide DNA methylation as one of the features playing a key role in psoriasis [21,29]. The study by Chandra revealed a significant difference in the enrichment of methylated CpGs in PSORS regions, where it shows an inverse correlation with higher gene expression [29]. A link between histopathological findings (such as Munro's microabscess, parakeratosis, and neutrophil accumulation) has also been established [29].…”

“…The study by Chandra revealed a significant difference in the enrichment of methylated CpGs in PSORS regions, where it shows an inverse correlation with higher gene expression [29]. A link between histopathological findings (such as Munro's microabscess, parakeratosis, and neutrophil accumulation) has also been established [29]. Zhao reports that global DNA methylation is significantly increased in peripheral blood mononuclear cells and skin lesions of psoriatic patients compared to healthy controls [21].…”

Evaluation of expression pattern of selected genes associated with IL12/23 signaling paths in psoriatic patients during cyclosporine A therapy

“…One of the most characteristic symptoms of this disease is the phenomenon of parakeratosis, that is, the keratosis of the epidermis being accelerated by about eight times the regular speed (Albanesi, ; Reali & Brembilla, ). The role and contribution of genetic, environmental, and epigenetic factors in the context of induction and development of psoriasis is widely discussed and analyzed (Chandra, Senapati, Roy, Chatterjee, & Chatterjee, ; Kimmel & Lebwohl, ). It seems that a key factor in understanding the nature of the inflammation underlying this disease is the assessment of changes at the molecular level (Hacker, Hoermann, & Kenner, ; Salto‐Tellez, ; Zhao et al, ).…”