Psoriasis is an inflammatory skin disorder with relapsing disposition in the skin of a patient (Di Meglio, Villanova et al. 2014; Chandra, Ray et al. 2015; Rendon and Schakel 2019). It has a global prevalence rate varying between 0.27 to 11.4% across different populations in the world (Chandran and Raychaudhuri 2010; Dogra and Yadav 2010; Gervin, Vigeland et al. 2012; Chandra, Ray et al. 2015). Psoriasis vulgaris is the most common form of the disease, which manifests in the form of well-demarcated reddish plaques on the skin surface, often encrusted with silvery-white scales (Lowes, Suarez-Farinas et al. 2014; Greb, Goldminz et al. 2016; Rendon and Schakel 2019). Psoriasis pathogenesis is attributed to a complex interplay between epidermal keratinocytes and skin-infiltrated immune cells resulting in keratinocyte hyperproliferation coupled with their abnormal differentiation (Lowes, Suarez-Farinas et al. 2014; Greb, Goldminz et al. 2016; Rendon and Schakel 2019; Griffiths, Armstrong et al. 2021). Several studies including genetic association, genome-wide association studies, linkage analysis, genomics and epigenomics have explicated a strong genetic predisposition, and involvement of environmental and epigenetic factors in the pathogenesis of Psoriasis {Chandra, 2015 #4; Nair, 2009 #16;Genetic Analysis of Psoriasis, 2010 #17;Zhang, 2002 #18;Zhang, 2009 #19;Tang, 2014 #20;Gudjonsson, 2012 #21;Roberson, 2012 #22;Chandra, 2016 #97;Chandra, 2017 #1;Chandra, 2018 #15;Frischknecht, 2019 #24;Zeng, 2021 #23;Chandra, 2021 #96; }. The fact that the disease phenotype on the skin can be reversed through treatment clearly shows that epigenetic and other non-genetic factors play an important role alongside genetic factors (Chandra, Senapati et al. 2018). Among the epigenetic modifications, DNA methylation is widely reported to be instrumental in keratinocyte differentiation, and the involvement of DNA methylation in Psoriasis has been elaborated by numerous studies (Chatterjee and Vinson 2012; Gudjonsson and Krueger 2012; Roberson, Liu et al. 2012; Zhang, Zhao et al. 2013; Frischknecht, Vecellio et al. 2019; Zeng, Tsoi et al. 2021). Several disease-specific genes are reported to be regulated by differential promoter methylation including S100A8, S100A9, PTPN22, SELENBP1 and DENND1C among others (Chandra, Senapati et al. 2018; Wang, Liu et al. 2020; Zeng, Tsoi et al. 2021; Mateu-Arrom and Puig 2023). Moreover, we have previously shown that DNA methylation is instrumental in regulating the cardinal histopathological features of Psoriasis (Chandra, Senapati et al. 2018). In addition to epigenetics, non-coding RNAs constitute another mode of gene regulation in Psoriasis by post-transcriptional gene silencing (Ghosh, Ganguly et al. 2023). The most prominent of these include miRNAs, a class of non-coding RNAs of length 18-22bp (Zibert, Lovendorf et al. 2010; Joyce, Zhou et al. 2011; Srivastava, Meisgen et al. 2019; Solvin, Chawla et al. 2022). MiRNAs have been widely implicated in the regulation of keratinocyte proliferation, differentiation and apoptosis (Bartel 2004; Timis and Orasan 2018; Xiuli and Honglin 2021). Recent studies have construed miRNA regulatory networks in facilitating epidermal hyperplasia, contributed both by upregulated and downregulated miRNAs which target key psoriasis-specific genes (Xiuli and Honglin 2021). In recent years, transcriptome, small RNA and methylation profiling have been conducted in psoriatic and normal skin tissues (Joyce, Zhou et al. 2011; Jabbari, Suarez-Farinas et al. 2012; Roberson, Liu et al. 2012; Li, Tsoi et al. 2014; Swindell, Sarkar et al. 2017; Chandra, Senapati et al. 2018; Verma, Ekman et al. 2018; Srivastava, Meisgen et al. 2019; Solvin, Chawla et al. 2022). However, most of these studies have focused on a solitary regulatory aspect. There is a paucity of multi-omics studies from the same patients, which could further illuminate the multi-factorial regulation of the disease.
In our study, for the first time, we have carried out multi-genomics integrative analysis of total-RNA-sequencing, small RNA-sequencing and genome-wide DNA methylation profiling on the same set of lesional psoriatic plaques and adjacent normal skin tissues. We have inspected the genes regulated by DNA methylation and miRNAs, and have explored the biological processes governed by these process in psoriasis. Furthermore, we have studied the pathways and gene enrichment maps depicting the singular and/or combinative regulation of significantly altered CpG methylation and miRNAs in Psoriasis. Interestingly genes related to cell cycle was almost entirely observed to be regulated by miRNAs, while CpG methylation had a more pronounced regulatory role in regulating immune and inflammatory responses. Several key psoriasis-specific pathways were found to be modulated by the combined effect of both regulatory mechanisms, including Th17 cell differentiation, a well-reported process in psoriasis pathogenesis (Greb, Goldminz et al. 2016; Rendon and Schakel 2019; Griffiths, Armstrong et al. 2021).