Human endogenous retroviruses sustain complex and cooperative regulation of gene-containing loci and unannotated megabase-sized regions.
BACKGROUND
Evidence suggests that some human endogenous retroviruses and endogenous retrovirus-like repeats (here collectively ERVs) regulate the expression of neighboring genes in normal and disease states; e.g. the human globin locus is regulated by an ERV9 that coordinates long-range gene switching during hematopoiesis and activates also intergenic transcripts. While complex transcription regulation is associated with integration of certain exogenous retroviruses, comparable regulation sustained by ERVs is less understood.


RESULTS
We analyzed ERV transcription using ERV9 consensus sequences and publically available RNA-sequencing, chromatin immunoprecipitation with sequencing (ChIP-seq) and cap analysis gene expression (CAGE) data from ENCODE. We discovered previously undescribed and advanced transcription regulation mechanisms in several human reference cell lines. We show that regulation by ERVs involves long-ranging activations including complex RNA splicing patterns, and transcription of large unannotated regions ranging in size from several hundred kb to around 1 Mb. Moreover, regulation was found to be cooperatively sustained in some loci by multiple ERVs and also non-LTR repeats.


CONCLUSIONS
Our analyses show that endogenous retroviruses sustain advanced transcription regulation in human cell lines, which shows similarities to complex insertional mutagenesis effects exerted by exogenous retroviruses. By exposing previously undescribed regulation effects, this study should prove useful for understanding fundamental transcription mechanisms resulting from evolutionary acquisition of retroviral sequence in the human genome.
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, DK-8000, Denmark. msokol@mb.au.dk.
Martin
M
Sokol
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, DK-8000, Denmark. karenmjessen@gmail.com.
Karen Margrethe
KM
Jessen
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, DK-8000, Denmark. fsp@mb.au.dk.
Finn Skou
FS
Pedersen
D002460:Cell Line; D020077:Endogenous Retroviruses / Q000235:genetics*; D005786:Gene Expression Regulation; D056426:Genetic Loci; D054884:Host-Pathogen Interactions; D006801:Humans; D012326:RNA Splicing; D014158:Transcription, Genetic