Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues

• Published in: Genome medicine Vol. 12; no. 1; p. 40
• Main Authors: Larouche, Jean-David, Trofimov, Assya, Hesnard, Leslie, Ehx, Gregory, Zhao, Qingchuan, Vincent, Krystel, Durette, Chantal, Gendron, Patrick, Laverdure, Jean-Philippe, Bonneil, Éric, Côté, Caroline, Lemieux, Sébastien, Thibault, Pierre, Perreault, Claude
• Format: Journal Article Web Resource
• Language: English
• Published: England BioMed Central Ltd 28.04.2020; BioMed Central; BMC
• Subjects: AIRE Protein; Amino acid composition; Amino Acid Sequence; Analysis; Animals; Archives & records; Autoimmune diseases; Autoimmunity; CD8-Positive T-Lymphocytes - drug effects; Cell differentiation; Cytokines - pharmacology; Datasets; Dendritic Cells; Deoxyribonucleic acid; DNA; Embryo cells; Embryonic stem cells; Endogenous retroelements; Epigenetics; Epithelial cells; Epithelial Cells - metabolism; Gene expression; Genetics & genetic processes; Genomes; Genomics; Génétique & processus génétiques; Homology; Humans; Immunogenicity; Immunological tolerance; Immunopeptidome; Life sciences; Lymphoblastoid cell lines; Major histocompatibility complex; Mass Spectrometry; Mass spectroscopy; Medullary thymic epithelial cells; Mice, Knockout; Peptides; Proteins; Retroelements; Ribonucleic acid; RNA; RNA sequencing; Sciences du vivant; Sequence Analysis, RNA; Somatic cells; Somatic tissues; Standard deviation; Stem cell transplantation; Stem cells; Systems biology; Thymus; Thymus Gland - cytology; Transcription Factors - genetics; Somatic tissues; Major histocompatibility complex; Medullary thymic epithelial cells; Systems biology; Immunopeptidome; Transcriptome; Endogenous retroelements
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-020-00740-7

Endogenous retroelements (EREs) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer. The dominant paradigm holds that EREs are expressed in embryonic stem cells (ESCs) and germline cells but are repressed in differentiated somatic cells. Despite evidence that some EREs can be expressed at the RNA and protein levels in specific contexts, a system-level evaluation of their expression in human tissues is lacking. Using RNA sequencing data, we analyzed ERE expression in 32 human tissues and cell types, including medullary thymic epithelial cells (mTECs). A tissue specificity index was computed to identify tissue-restricted ERE families. We also analyzed the transcriptome of mTECs in wild-type and autoimmune regulator (AIRE)-deficient mice. Finally, we developed a proteogenomic workflow combining RNA sequencing and mass spectrometry (MS) in order to evaluate whether EREs might be translated and generate MHC I-associated peptides (MAP) in B-lymphoblastoid cell lines (B-LCL) from 16 individuals. We report that all human tissues express EREs, but the breadth and magnitude of ERE expression are very heterogeneous from one tissue to another. ERE expression was particularly high in two MHC I-deficient tissues (ESCs and testis) and one MHC I-expressing tissue, mTECs. In mutant mice, we report that the exceptional expression of EREs in mTECs was AIRE-independent. MS analyses identified 103 non-redundant ERE-derived MAPs (ereMAPs) in B-LCLs. These ereMAPs preferentially derived from sense translation of intronic EREs. Notably, detailed analyses of their amino acid composition revealed that ERE-derived MAPs presented homology to viral MAPs. This study shows that ERE expression in somatic tissues is more pervasive and heterogeneous than anticipated. The high and diversified expression of EREs in mTECs and their ability to generate MAPs suggest that EREs may play an important role in the establishment of self-tolerance. The viral-like properties of ERE-derived MAPs suggest that those not expressed in mTECs can be highly immunogenic.