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

Abstract

Dysregulated endogenous retroelements (EREs) are increasingly implicated in the initiation, progression, and immune surveillance of human cancer. However, incomplete knowledge of ERE activity limits mechanistic studies. By using pan-cancer de novo transcript assembly, we uncover the extent and complexity of ERE transcription. The current assembly doubled the number of previously annotated transcripts overlapping with long-terminal repeat (LTR) elements, several thousand of which were expressed specifically in one or a few related cancer types. Exemplified in melanoma, LTR-overlapping transcripts were highly predictable, disease prognostic, and closely linked with molecularly defined subtypes. They further showed the potential to affect disease-relevant genes, as well as produce novel cancer-specific antigenic peptides. This extended view of LTR elements provides the framework for functional validation of affected genes and targets for cancer immunotherapy.

Endogenous retroviruses drive KRAB zinc-finger family protein expression for tumor suppression

“…In nine out of the twelve types of cancers, the overall expression levels of HERVs were increased compared to that in the adjacent normal tissues ( Fig. 1B ), consistent with previous reports 20–24 . Dimension reduction analysis based on HERV expression profiles showed that each type of cancer displays a distinguishable pattern of HERV expression ( Fig.…”

“…The expression of HERVs in normal tissues is controlled by epigenetic mechanisms such as DNA methylation and repressive histone modifications 18,19 ; in contrast, HERV expression is highly elevated in various types of cancers 20–24 . Since the elevation of HERV expression in tumors is presumably caused by epigenetic reactivation, the expressed HERVs could upregulate the expression of adjacent genes.…”

Tissue-specific and interferon-inducible expression of non-functional ACE2 through endogenous retrovirus co-option

“…Our recent de novo cancer transcriptome assembly (Attig et al, 2019) identified a chimeric transcript between annotated exons of ACE2 and an LTR16A1 retroelement, integrated in intron 9 of the ACE2 locus. This transcript, which we refer to here as LTR16A1-ACE2, is initiated at the LTR16A1 retroelement, which functions as a cryptic promoter and includes exons 10-19 of ACE2 ( Figure 1A).…”

“…Transcripts were previously assembled on a subset of the RNAseq data from The Cancer Genome Atlas (TCGA) (Attig et al, 2019). The alternative promoter within ACE2 was more highly expressed in lung squamous carcinomas than the canonical isoform, prompting us to investigate its biology.…”

“…Using our recent de novo transcriptome assembly (Attig et al, 2019), we identify a novel, truncated ACE2 transcript, termed LTR16A1-ACE2, initiated at an intronic LTR16A1 retroelement that serves as a cryptic promoter. Strikingly, we find that the truncated LTR16A1-ACE2 and not full-length ACE2 is the interferon-inducible isoform, and is strongly upregulated in viral infection and following interferon treatment.…”