Physiological and Pathological Transcriptional Activation of Endogenous Retroelements Assessed by RNA-Sequencing of B Lymphocytes

Abstract

In addition to evolutionarily-accrued sequence mutation or deletion, endogenous retroelements (EREs) in eukaryotic genomes are subject to epigenetic silencing, preventing or reducing their transcription, particularly in the germplasm. Nevertheless, transcriptional activation of EREs, including endogenous retroviruses (ERVs) and long interspersed nuclear elements (LINEs), is observed in somatic cells, variably upon cellular differentiation and frequently upon cellular transformation. ERE transcription is modulated during physiological and pathological immune cell activation, as well as in immune cell cancers. However, our understanding of the potential consequences of such modulation remains incomplete, partly due to the relative scarcity of information regarding genome-wide ERE transcriptional patterns in immune cells. Here, we describe a methodology that allows probing RNA-sequencing (RNA-seq) data for genome-wide expression of EREs in murine and human cells. Our analysis of B cells reveals that their transcriptional response during immune activation is dominated by induction of gene transcription, and that EREs respond to a much lesser extent. The transcriptional activity of the majority of EREs is either unaffected or reduced by B cell activation both in mice and humans, albeit LINEs appear considerably more responsive in the latter host. Nevertheless, a small number of highly distinct ERVs are strongly and consistently induced during B cell activation. Importantly, this pattern contrasts starkly with B cell transformation, which exhibits widespread induction of EREs, including ERVs that minimally overlap with those responsive to immune stimulation. The distinctive patterns of ERE induction suggest different underlying mechanisms and will help separate physiological from pathological expression.

Endogenous Retroviruses as Genetic Modules That Shape the Genome Regulatory Networks During Evolution

“…At the same time, species-specific ERVs capable of tissue-specific activation are an excellent tool for creating new regulatory elements and genetic programs in the evolution process. Experimental data confirm the role of endogenous retroviruses in the formation of alternative promoters and enhancers, as well as genes of long non-coding RNAs and the role in the reformatting of regulatory networks [29][30][31][32][33].…”

“…A small number of LTR elements, which are constantly activated in stimulated B cells, are detected, with one of the Xmv45 retroviruses being expressed in a larger amount than the rest of them combined. The expression of a large number ERVs is at the same time activated during B cell transformation [33].…”

LTR retroelement expansion of the human cancer transcriptome and immunopeptidome revealed by de novo transcript assembly

“…LTR and non-LTR elements were annotated as described previously (Attig et al 2017) and in the Supplemental Methods.…”

Tissue-specific and interferon-inducible expression of nonfunctional ACE2 through endogenous retroelement co-option

“…At the transcriptional level, long terminal repeats (LTRs), derived from endogenous retroviruses and other LTR retroelements, as well as regulatory sequences in non-LTR retroelements, serve as cis-regulatory enhancers for a number of ISGs and are required for their induction 7 . Adding to this regulatory complexity, many retroelements are themselves IFN-responsive promoters and are upregulated following viral infection or in IFN-driven autoimmunity [8][9][10][11] .…”