The lupus susceptibility locus Sgp3 encodes the suppressor of endogenous retrovirus expression SNERV

Treger, Rebecca S.; Pope, Scott D.; Kong, Yong; Tokuyama, Maria; Taura, Manabu; Iwasaki, Akiko

doi:10.1101/487231

Cited by 19 publications

(27 citation statements)

References 87 publications

(96 reference statements)

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“…Hundreds of scientific articles have alluded to the potential implication of EREs in various human diseases, particularly cancer and autoimmunity [2,[66][67][68][69][70][71]. We therefore felt compelled to draw the global landscape of ERE expression in human somatic cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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 systemlevel 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 Blymphoblastoid 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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…ERVs and anti-ERV autoreactivity have been implicated in the pathogenesis of lupus and other autoimmune diseases. Expression of the ERV glycoprotein gp70 results in nephritis caused by immune complex deposition in lupus mouse models, and a reduction in ERV silencing proteins is associated with elevated ERV expression in mice and human lupus 208 . Hepatocyte ERV gp70 expression can be induced by translocation of the gut pathobiont E. gallinarum to the liver of lupus-prone mice 11 .…”

Section: Transkingdom Interactionsmentioning

confidence: 99%

Host–microbiota interactions in immune-mediated diseases

2020

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The immune system evolved not only to fend off pathogens but also to tolerate beneficial microbiota that evolved to live in symbiosis with the host 1. This is perhaps best exemplified from an immunological viewpoint by the paradigm that not only self but also commensal antigens are recognized by regulatory T (T reg) cells that suppress pathological immune responses 2,3. Thus, under immune homeostasis, the immune system tolerates beneficial commensal bacteria but can respond to these same microbiota during tissue disruption or other homeostatic perturbations 4. Self-non-self discrimination of host antigens is a fundamental process that is established and maintained by well-defined central and peripheral tolerance mechanisms (Box 1). How the host immune system develops and responds to the microbiota remains an immunological conundrum of self-non-self discrimination that is poorly understood. Immune-mediated diseases develop in genetically prone individuals when tolerance mechanisms are broken. These diseases are characterized by immunologically mediated tissue damage that is either directed against self-antigens (autoimmunity), transplanted or transfused antigens (alloimmunity), innocuous environmental agents that are inhaled or ingested (allergy) or in the absence of specific antigens (autoinflammation) (Box 2). It is increasingly appreciated that the microbiota directly and indirectly modulates tolerogenic processes that keep inflammatory responses in check. These responses may occur at barrier surfaces

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“…A recent comparative RNA-seq study between B6J and C57BL/6N (B6N) found that the majority of differentially expressed loci between these two sub-strains were NEERVs; the ERV envelope protein and NEERV gene expression were significantly higher in B6N compared to B6J [ 70 ]. F1 hybrid mice showed low NEERV gene expression and ERV envelope protein levels that were comparable to B6J mice, indicating the presence of a dominant NEERV repressor in the B6J sub-strain.…”

Section: Evidence Of Strain-specific Erv Controlmentioning

confidence: 99%

“…Aside from the NEERV effectors, 2410141K09Rik and Gm10324 , specific modifiers for the other ERVs subject to strain-specific regulation are yet to be identified. It is worth noting that many of the modifiers linked to strain-specific ERV regulation reside on Chromosome 13 and overlap known KRAB-ZFP clusters, one of which includes KRAB-ZFPs Rsl1 and Rsl2 ( Figure 2 and Table 1 ) [ 66 , 70 , 76 , 117 ]. Rsl1 and Rsl2 are strain-specific KRAB-ZFPs that regulate sexually dimorphic gene expression in the liver.…”

Section: Krab-zfps As Effectors Of Strain-specific Erv Regulationmentioning

confidence: 99%

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

Elmer

Ferguson‐Smith

2020

Viruses

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Approximately 10 percent of the mouse genome consists of endogenous retroviruses (ERVs), relics of ancient retroviral infections that are classified based on their relatedness to exogenous retroviral genera. Because of the ability of ERVs to retrotranspose, as well as their cis-acting regulatory potential due to functional elements located within the elements, mammalian ERVs are generally subject to epigenetic silencing by DNA methylation and repressive histone modifications. The mobilisation and expansion of ERV elements is strain-specific, leading to ERVs being highly polymorphic between inbred mouse strains, hinting at the possibility of the strain-specific regulation of ERVs. In this review, we describe the existing evidence of mouse strain-specific epigenetic control of ERVs and discuss the implications of differential ERV regulation on epigenetic inheritance models. We consider Krüppel-associated box domain (KRAB) zinc finger proteins as likely candidates for strain-specific ERV modifiers, drawing on insights gained from the study of the strain-specific behaviour of transgenes. We conclude by considering the coevolution of KRAB zinc finger proteins and actively transposing ERV elements, and highlight the importance of cross-strain studies in elucidating the mechanisms and consequences of strain-specific ERV regulation.

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The lupus susceptibility locus Sgp3 encodes the suppressor of endogenous retrovirus expression SNERV

Cited by 19 publications

References 87 publications

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

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

Host–microbiota interactions in immune-mediated diseases

Strain-Specific Epigenetic Regulation of Endogenous Retroviruses: The Role of Trans-Acting Modifiers

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