513 Regulatory roles of lncRNAs in psoriasis determined by single cell analysis

Abstract

Long noncoding RNAs (lncRNAs) can harbor DNA binding domains and regulate target gene expressions by binding to their promoter regions. Although a large proportion of differentially expressed lncRNAs have been identified in psoriatic skin, a chronic inflammatory disease enriched in pro-inflammatory genes, their cell type and disease specificity are yet to be revealed. We performed scRNA-seq experiments in non-lesional skin and lesional skin from 6 psoriasis patients, and compared the expression profiles of lncRNAs against skin from 5 control samples. Most of the up-regulated lncRNA were enriched in keratinocytes (for example, MALAT1 and NEAT1), fibroblasts (MEG3), or melanocytes (KU-MEL-3). However, many of these differentially expressed lncRNAs do not yet have known functional roles. We conducted a in silico analysis to assay the DNA binding ability for 121 differentially expressed lncRNA in psoriasis lesional/non-lesional against control (FDR<=5%) within each of the 12 cell types, revealing 5,879 potential downstream protein-coding gene targets. We identified that the lncRNAs NEAT1 and MALAT1 (known to perform regulatory roles) targets include epidermal genes such as: PPP1R15A, ZFP36, and SFN, which are responsible for cell cycle regulation and cell proliferation. Notably, these target genes are all correlated with MALAT1 and NEAT only in the lesional skin, but not the non-lesional/control keratinocytes. In addition, MALAT1 is also co-expressed with other binding targets JUN, and JUNB, which are involved in pro-inflammatory response within psoriasis (R≥0.35, p<2.2e-16). Interestingly, within the control and non-lesional keratinocytes, MALAT1 expression was negatively correlated with binding targets including DMKN (pro-inflammatory), and FABP5(proliferation gene) (R<= 0.4, p<2.2e-16). Together, these findings highlight how insight from co-expression analysis can contextualize the functional role of lncRNAs within a gene regulatory network.