Background/Purpose: Gene expression studies of peripheral blood mononuclear cells in SLE have consistently shown an interferon signature.  We previously examined monocytes from SLE patients to understand the impact of interferon expression on the cell that is integral to atherosclerosis and renal disease.  In that study, we also found a gene expression signature consistent with interferon exposure.  Various triggers of interferon expression have been identified and endogenous retroviral elements have been considered as a possible nucleic acid stimulus.  Older literature on endogenous retroviruses in SLE identified intracisternal A-type particles reminiscent of retroviruses and frequent identification of anti-retroviral antibodies.  Nevertheless, there has been little direct demonstration of altered expression of endogenous retroviral elements.  To better understand the altered gene expression and to examine non-coding RNAs, which are poorly represented on arrays, we performed RNA-seq.

Methods:  RNA-seq on the SOLiD platform was performed on RNA from monocytes from 8 SLE patients and 8 age/gender-matched controls.  Reads were aligned and mapped using BioScope.  .  The biological samples were scored to define variability by calculating the sample-sample correlation. Group comparison statistics and FDR calculation were used to identify regions with significant RPKM group-based variations.   To minimize confounders, we selected patients with a low disease activity and minimal medications.

Results: Again, we saw evidence of interferon exposure.  We also noted a dramatic enrichment of genes regulated by the IRF family of transcription factors.  Among the most highly expressed transcripts were non-coding RNAs, anti-sense RNAs and micro-RNAs, suggesting that array studies have captured but one facet of the transcriptome.  The use of RNA-seq also enabled us to look at highly repetitive transcripts such as LINE and Alu elements. Although unmappable, the total read depth was analyzed.  Amongst all repetitive elements, the ERVK family was found to be 3X overexpressed in SLE monocytes relative to the controls.  Other engogenous retroviral elements were expressed at comparable levels in SLE patient and controls. 

Conclusion: The ERVK family of endogenous retroviruses is unusual in that it can encode gag, env, pol, reverse transcriptase and integrase proteins.  Retroviruses have been implicated in murine lupus but data on human endogenous retroviruses have been limited.  The recognition of the important role of TREX1 in limiting retroviral DNA induction of interferons has supported a role for retroviruses in human SLE but until the advent of next generation sequencing, it was difficult to identify specific families.  This study identified many non-coding RNAs both over-expressed and under-expressed, often by 20-50-fold.  Unexpectedly, the ERVK family was over-expressed out of proportion to other endogenous retroviruses, suggesting that this family may be selectively de-repressed.  De-repression of ERVK elements could contribute to interferon production via accumulation of viral RNAs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/systemic-lupus-erythematosus-rna-seq-endogenous-retroviral-group-k-overexpression-in-monocytes/