RNA-seq identifies a diminished differentiation gene signature in primary monolayer keratinocytes grown from lesional and uninvolved psoriatic skin

Keratinocyte (KC) hyper-proliferation and epidermal thickening are characteristic features of psoriasis lesions, but the specific contributions of KCs to plaque formation are not fully understood. This study used RNA-seq to investigate the transcriptome of primary monolayer KC cultures grown from lesional (PP) and non-lesional (PN) biopsies of psoriasis patients and control subjects (NN). Whole skin biopsies from the same subjects were evaluated concurrently. RNA-seq analysis of whole skin identified a larger number of psoriasis-increased differentially expressed genes (DEGs), but analysis of KC cultures identified more PP- and PN-decreased DEGs. These latter DEG sets overlapped more strongly with genes near loci identified by psoriasis genome-wide association studies and were enriched for genes associated with epidermal differentiation. Consistent with this, the frequency of AP-1 motifs was elevated in regions upstream of PN-KC-decreased DEGs. A subset of these genes belonged to the same co-expression module, mapped to the epidermal differentiation complex, and exhibited differentiation-dependent expression. These findings demonstrate a decreased differentiation gene signature in PP/PN-KCs that had not been identified by pre-genomic studies of patient-derived monolayers. This may reflect intrinsic defects limiting psoriatic KC differentiation capacity, which may contribute to compromised barrier function in normal-appearing uninvolved psoriatic skin. Samples were obtained from lesional skin of psoriasis patients (PP), uninvolved skin of psoriasis patients (PN), and normal skin from control individuals (NN). RNA was extracted from full-thickness skin biopsies of keratinocytes (KCs) grown as monolayer cutures. Samples were obtained from 4 psoriasis patients (individuals 1 - 4) and 4 control subjects (individuals 5 - 8).