Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues
Abstract Background 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 d...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-04-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13073-020-00740-7 |
| _version_ | 1818252180130365440 |
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| author | Jean-David Larouche Assya Trofimov Leslie Hesnard Gregory Ehx Qingchuan Zhao Krystel Vincent Chantal Durette Patrick Gendron Jean-Philippe Laverdure Éric Bonneil Caroline Côté Sébastien Lemieux Pierre Thibault Claude Perreault |
| author_facet | Jean-David Larouche Assya Trofimov Leslie Hesnard Gregory Ehx Qingchuan Zhao Krystel Vincent Chantal Durette Patrick Gendron Jean-Philippe Laverdure Éric Bonneil Caroline Côté Sébastien Lemieux Pierre Thibault Claude Perreault |
| author_sort | Jean-David Larouche |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| first_indexed | 2024-12-12T16:20:04Z |
| format | Article |
| id | doaj.art-d473cb8940d0454994221bb51e7f2e8e |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-12T16:20:04Z |
| publishDate | 2020-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-d473cb8940d0454994221bb51e7f2e8e2022-12-22T00:19:01ZengBMCGenome Medicine1756-994X2020-04-0112111610.1186/s13073-020-00740-7Widespread and tissue-specific expression of endogenous retroelements in human somatic tissuesJean-David Larouche0Assya Trofimov1Leslie Hesnard2Gregory Ehx3Qingchuan Zhao4Krystel Vincent5Chantal Durette6Patrick Gendron7Jean-Philippe Laverdure8Éric Bonneil9Caroline Côté10Sébastien Lemieux11Pierre Thibault12Claude Perreault13Institute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalInstitute of Research in Immunology and Cancer, Université de MontréalAbstract Background 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. Methods 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. Results 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. Conclusions 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.http://link.springer.com/article/10.1186/s13073-020-00740-7Endogenous retroelementsImmunopeptidomeMajor histocompatibility complexMedullary thymic epithelial cellsSomatic tissuesSystems biology |
| spellingShingle | Jean-David Larouche Assya Trofimov Leslie Hesnard Gregory Ehx Qingchuan Zhao Krystel Vincent Chantal Durette Patrick Gendron Jean-Philippe Laverdure Éric Bonneil Caroline Côté Sébastien Lemieux Pierre Thibault Claude Perreault Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues Genome Medicine Endogenous retroelements Immunopeptidome Major histocompatibility complex Medullary thymic epithelial cells Somatic tissues Systems biology |
| title | Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues |
| title_full | Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues |
| title_fullStr | Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues |
| title_full_unstemmed | Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues |
| title_short | Widespread and tissue-specific expression of endogenous retroelements in human somatic tissues |
| title_sort | widespread and tissue specific expression of endogenous retroelements in human somatic tissues |
| topic | Endogenous retroelements Immunopeptidome Major histocompatibility complex Medullary thymic epithelial cells Somatic tissues Systems biology |
| url | http://link.springer.com/article/10.1186/s13073-020-00740-7 |
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