Abstract
BackgroundEndogenous 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.MethodsUsing 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.ResultsWe 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.ConclusionsThis 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.
Highlights
Endogenous retroelements (EREs) constitute about 42% of the human genome and have been implicated in common human diseases such as autoimmunity and cancer
In summary, transcriptomic analysis demonstrated that ERE expression is heterogeneous in healthy human tissues, with a higher expression in Medullary thymic epithelial cells (mTEC), Embryonic stem cells (ESC), and testis than in other tissues. mTECs are the sole normal human cells that express high levels of both EREs and MHC I molecules
We report that the exceptional expression of EREs in mTECs is AIREindependent
Summary
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. Endogenous retroelements (EREs) are remnants of transposable elements that successfully integrated our germline DNA millions of years ago [1, 2]. A strict epigenetic regulation of ERE sequences is applied at both the DNA and histone levels [12]. Growing evidence suggests that KRAB zinc finger proteins (KZFPs) are involved in an evolutionary arms race to repress the expression of novel ERE integrations [13]. ERE sequences are key components of several promoters and enhancers of genes implicated in interferon responses, DNA damage response in the male germline, and maintenance of stem cell pluripotency [17,18,19]. Syncytins are ERE-derived proteins that mediate cell-cell fusion to allow the formation of the placental syncytium [21, 22]
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