## 2 Large Cohort Transcriptome Analysis of Psoriasis
A similar array-based gene expression studies, comparing 15 psoriasis patients and healthy controls, by [PERSON] et al. identified a total of 177 genes differentially expressed in lesional skin versus normal skin [32]. One of the first gene expression studies that compared skin lesions of atopic dermatitis (AD) and psoriasis reported a significant upregulation of 62 genes, including CCL4, CCL20, CXCL2, CXCL8, and CXCR2, in the psoriatic skin, while around 18 genes were upregulated in AD skin [33]. Overlapping of around 2000 genes (including CCL-2/3/17/18, IL-6/8/17A/22/23A, S100A9/A15, TRPV1, and PLA2) unique to psoriatic, lesional atopic skin, compared with healthy skin, were identified from a recent RNA-seq analysis from 25 psoriatic and AD skin patients [34]. Such studies provide more insights to the characteristic disease signature of both these skin diseases [34]. Several lines of evidence suggests that keratinocytes (KC) are the main drivers in the development of psoriasis in response to activated immune cascade [7; 8]. Studies by [PERSON] et al. and [PERSON] et al. have identified that many of the genes upregulated in psoriatic skin were involved on epidermal organization and differentiation, highlighting the role of keratinocytes in the pathogenesis of psoriasis [35; 36]. Several in vitro studies based on cytokine stimulation of keratinocytes have also provided insights to the cellular sources of the gene expression in psoriasis [20; 37; 38; 39; 40]. Establishing an in vitro psoriasis KC model by stimulating Hacet keratinocytes with an M5 cytokine cocktail (IL17A, TNF\(\alpha\), Oncostatin, IL22, and IL1\(\alpha\)) resulted in strong transcriptional regulation of chemokines, including CXCL1, CXCL2, CXCL8, CCL20, and CCL27, as well as antimicrobial peptides S100A7, S100A8, S100A9, S100A12, LL-37, and Beta Defensin-2 [37]. However, one of the main limitations of such in vitro models, involving monolayer keratinocytes, is that they may not fully recapitulate psoriatic features present in psoriatic lesions and uninvolved psoriatic skin. One early study comprising a large cohort of lesional vs. non-lesional transcriptomic profiling was performed by [PERSON] et al., in which they analysed 58 paired samples of lesional and non-lesional skin in comparison with 64 control biopsies [41]. Some of the strongly upregulated genes included SERPIN84, PI3, DEFB4, and several S100 family members. This study also reported significant dysregulation of genes involved in lipid and fatty acid metabolism, including transcription factors PPARA, ESR2, and SEBF1, linked to impaired lipid metabolism. An interesting observation noted in this study was that uninvolved psoriatic skin often exists in a \"pre- psoriatic\" state. When compared to already reported/published transcriptomes of cytokine stimulated cultured keratinocytes, there was little overlap in the gene expression data with the lesional psoriatic dysregulated transcriptome [20; 37; 38; 39]. A very recent study by [PERSON] et al. studied the keratinocyte-specific gene expression changes in lesional and non-lesional psoriasis skin, and the results presented in this study show evidence for the dominance of an IL-22/IL-17A signature in psoriatic keratinocytes with the contribution of the IL-1/IL-36 and IL-20 families [42]. Molecular heterogeneity between various subtypes of plaque psoriasis was studied by [PERSON] et al. on skin samples from individuals with scalp, palmolantar, and conventional plaque psoriasis compared with healthy controls. Around 763 differentially expressed genes, including S100A7A, S100A9, SERPINB4, KRT6, SPRR2A/B, C10 orf99, II36v, and late cornified envelope proteins associated with keratinocyte proliferation and activation, were reported. [39]. Studies have investigated RNA expression patterns across lesional and non-lesional tissue samples vs. healthy controls. Decision tree predictors to differentiate psoriatic samples based on gene expression patterns were studied by [PERSON] et al., which revealed distinct molecular sub-groups of plaque psoriasis.