Transcriptional landscape of human endogenous retroviruses (HERVs) and other repetitive elements in psoriatic skin

Abstract

Human endogenous retrovirus (HERV) sequences make up at least 8% of the human genome. Transcripts originating from these loci as well as proteins encoded by them have been detected in various tissues. HERVs are believed to be implicated in autoimmune diseases, however the extent to which, has remained unclear. Differential expression studies have so far been limited to certain HERV subfamilies with conserved sequences. No studies have been published describing the genome-wide expression pattern of HERVs and repetitive elements in the context of psoriasis. In the present study, we analysed total RNA sequencing data from skin samples of 12 psoriasis patients and 12 healthy controls, which enabled us to describe the entire transcriptional landscape of repetitive elements. We report high levels of repetitive element expression in the skin of psoriasis patients as well as healthy controls. The majority of differentially expressed elements were downregulated in lesional and non-lesional skin, suggesting active HERV suppression in the pro-inflammatory environment of psoriatic skin. However, we also report upregulation of a small subset of HERVs previously described in the context of autoimmune diseases, such as members of the HERV-K and W families, with the potential to affect the immunopathogenesis of psoriasis.

Figure 1

Differentially expressed elements in the lesional, non-lesional and healthy control skin. Expression levels of differentially expressed elements at FDR ≤ 0.01 in lesional skin (LP) vs control group or non-lesional skin (NLP) vs control group (C) comparisons are presented as a heatmap. Samples are clustered based on Euclidean distance calculated from z-score values. For every repetitive element, the mean and standard deviation based on control group CPM values were used for z-score calculation. Selection of patient traits are also presented: Psoriasis Area Severity Index (PASI) score, age, body mass index (BMI), course of the disease, sex and smoking status. Repetitive element classes are color coded. This information was not available for all control group individuals.

Figure 2

Differentially expressed elements in the lesional and non-lesional skin. (a) Distribution of foldchange values as logarithms to the base 2 (log₂FC) of differentially expressed elements in the pairwise comparison between lesional (LP) and non-lesional (NLP) skin of psoriasis patients. Only differentially expressed elements at FDR ≤ 0.01 are presented. (b) Log₂FC values of differentially expressed elements at FDR ≤ 0.01 in the pairwise comparison limited to log₂FC ≤ −0.5 or log₂FC ≥ 0.5 (translating into foldchange greater than 0.71 or 1.41). (c) PCA analysis based on counts per million (CPM) values of elements differentially expressed at FDR ≤ 0.01 in the LP vs C and NLP vs C comparisons. Plotted ovals represent the 95% confidence interval.

Figure 3

Coverage of HERVs relevant in psoriasis. Comparison of counts per million (CPM) values and sequence coverage of elements regarded relevant in psoriasis. (a) CPM values of HERV-K elements summarized at the family level. (b) Coverage data from all sequence loci of HERV-K elements displayed along the length of aligned sequences (x-axis) and on y-axis as log₁₀ of read depth. (c) CPM values of HERV-K11D. (d) Coverage data from all HERV-K11D loci displayed along the length of aligned sequences (x-axis) and on y-axis as log₁₀ of read depth. (e) CPM values of HERV-K14C (f) Coverage data from all HERV-K14C loci displayed along the length of aligned sequences (x-axis) and on y-axis as log₁₀ of read depth. (g) CPM values of the ERV9/HERV-W element and (h) coverage data displayed along the length of the sequences (x-axis) and on y-axis as log₁₀ of read depth. The study groups are marked “LP” for lesional skin on psoriasis patients, “NLP” for non-lesional skin of psoriasis patients and “C” for healthy controls.