Expression of APOBEC family members as regulators of endogenous retroelements and malignant transformation in systemic autoimmunity

Mavragani, Clio P.; Kirou, Kyriakos A.; Nezos, Adrianos; Seshan, Surya V.; Wild, Teresa; Wahl, Sharon M.; Moutsopoulos, Haralampos Μ.; Crow, Mary K.

doi:10.1016/j.clim.2020.108649

Cited by 12 publications

(11 citation statements)

References 60 publications

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“…Epigenomic modifications play a crucial role in autoimmunity, and hypomethylation was demonstrated to increase LINE-1 endogenous retroelements in SLE and SS [59] (Figure 2). In minor salivary gland tissue from SS patients, increased LINE-1 retroelement and interferon levels were shown to correlate with elevated expression of A3A, A3G, and AICDA genes [58]. The same was observed in kidney tissue and peripheral blood mononuclear cells of SLE patients for A3A [58].…”

Section: Genomic and Epigenomic Contributions Of Apobecs To Immune Pathologymentioning

confidence: 64%

“…In minor salivary gland tissue from SS patients, increased LINE-1 retroelement and interferon levels were shown to correlate with elevated expression of A3A, A3G, and AICDA genes [58]. The same was observed in kidney tissue and peripheral blood mononuclear cells of SLE patients for A3A [58]. In addition, high-throughput sequencing data from SLE patients reveal high global APOBEC expression, which might be a source for autoantigens in SLE [21] (Figure 3E).…”

Section: Genomic and Epigenomic Contributions Of Apobecs To Immune Pathologymentioning

confidence: 67%

“…APOBEC deaminases have also shown to contribute epigenetically to autoimmune diseases such as systemic lupus erythematosus (SLE) [57] and primary Sjörgren's syndrome (SS) [58]. Epigenomic modifications play a crucial role in autoimmunity, and hypomethylation was demonstrated to increase LINE-1 endogenous retroelements in SLE and SS [59] (Figure 2).…”

Section: Genomic and Epigenomic Contributions Of Apobecs To Immune Pathologymentioning

confidence: 99%

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APOBECs orchestrate genomic and epigenomic editing across health and disease

et al. 2021

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APOBEC proteins can deaminate cytosine residues in DNA and RNA. This can lead to somatic mutations, DNA breaks, RNA modifications, or DNA demethylation in a selective manner. APOBECs function in various cellular compartments and recognize different nucleic acid motifs and structures. They orchestrate a wide array of genomic and epigenomic modifications, thereby affecting various cellular functions positively or negatively, including immune editing, viral and retroelement restriction, DNA damage responses, DNA demethylation, gene expression, and tissue homeostasis. Furthermore, the cumulative increase in genomic and epigenomic editing with aging could also, at least in part, be attributed to APOBEC function. We synthesize our cumulative understanding of APOBEC activity in a unifying overview and discuss their genomic and epigenomic impact in physiological, pathological, and technological contexts. HighlightsGenomic and epigenomic effects of apolipoprotein B mRNA editing cytosine deaminases (APOBECs) are tightly controlled and are essential for physiological immune and non-immune processes.Pathological APOBEC off-target effects are often observed because of altered catalytic activity or dysregulation, and/or synergies with other predisposing factors such as infections, inflammation, or DNA repair defects.APOBEC mutation signatures are documented in various cancers. They are also involved in autoimmune diseases, triple nucleotide repeat diseases, and diabetes, among others.Possible APOBEC signatures in aging tissues also highlight their potential contribution to this process at the genomic and epigenomic levels.Advances in gene-editing technologies combined with APOBEC mechanistic insights are ushering in the era of APOBECs as therapeutic targets, potentially closing the loop of negative versus positive gene-editing effects.

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Section: Genomic and Epigenomic Contributions Of Apobecs To Immune Pathologymentioning

confidence: 64%

Section: Genomic and Epigenomic Contributions Of Apobecs To Immune Pathologymentioning

confidence: 67%

Section: Genomic and Epigenomic Contributions Of Apobecs To Immune Pathologymentioning

confidence: 99%

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APOBECs orchestrate genomic and epigenomic editing across health and disease

et al. 2021

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“…A3G inhibits retrovirus replication and the retrotransposition of HERVs [ 65 ]. The A3G and other A3 RNAs were overexpressed in the serum of SLE patients compared to healthy controls [ 66 ] and in the minor salivary glands of patients with Sjogren’s Syndrome lymphoma [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus

Bumiller-Bini

Kohler

Augusto

et al. 2022

Viruses

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The long search for the environmental trigger of the endemic pemphigus foliaceus (EPF, fogo selvagem) has not yet resulted in any tangible findings. Here, we searched for genetic associations and the differential expression of host genes involved in early viral infections and innate antiviral defense. Genetic variants could alter the structure, expression sites, or levels of the gene products, impacting their functions. By analyzing 3063 variants of 166 candidate genes in 227 EPF patients and 194 controls, we found 12 variants within 11 genes associated with differential susceptibility (p < 0.005) to EPF. The products of genes TRIM5, TPCN2, EIF4E, EIF4E3, NUP37, NUP50, NUP88, TPR, USP15, IRF8, and JAK1 are involved in different mechanisms of viral control, for example, the regulation of viral entry into the host cell or recognition of viral nucleic acids and proteins. Only two of nine variants were also associated in an independent German cohort of sporadic PF (75 patients, 150 controls), aligning with our hypothesis that antiviral host genes play a major role in EPF due to a specific virus–human interaction in the endemic region. Moreover, CCL5, P4HB, and APOBEC3G mRNA levels were increased (p < 0.001) in CD4+ T lymphocytes of EPF patients. Because there is limited or no evidence that these genes are involved in autoimmunity, their crucial role in antiviral responses and the associations that we observed support the hypothesis of a viral trigger for EPF, presumably a still unnoticed flavivirus. This work opens new frontiers in searching for the trigger of EPF, with the potential to advance translational research that aims for disease prevention and treatment.

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“…It is worth noting that the HERV expression follows the same kinetics of the expression of APOBECs, HRFs that play a determinant role in the control of retroviral infections (27). Given the role of APOBECs in cell biology (28), their possible impact in T cell selection deserves exploration. The same observation has been reported in the peripheral blood, particularly in patients with autoimmune diseases, namely systemic lupus erythematous and Sjogren Syndrome (15,29,30).…”

Section: Discussionmentioning

confidence: 99%

Expression of Human Endogenous Retroviruses in the Human Thymus Along T Cell Development

et al. 2022

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Human Endogenous Retroviruses (HERVs) constitute up to 8% of the human genome and have been emerging as important modulators of the immune system, being associated with cancer, autoimmunity and infectious diseases. Here, we investigated the expression of three HERV families in the human thymus. HERV-K, -W, and -R envelope (env) and HERV-K gag transcriptional levels were quantified in the main thymocyte subsets, thymic epithelial cells (TECs), B cells and myeloid populations, and Env protein expression was studied in thymic tissue. We found that HERV mRNA decreased with T cell development, which was in agreement with the identification of HERV-K Env protein in CD3 negative cortical cells. These results suggest a distinct regulation of HERV expression along T cell development, prompting us to evaluate the interplay with host restriction factors and potential underlying pathways. The transcriptional levels of some HERVs were found to positively correlate with the expression of the host restriction factors APOBEC3G and SLFN11, and, conversely, a negative correlation was found with SAMHD1. Moreover, IFN-α and IFN-γ induced the upregulation of HERV-K env and gag in purified CD4 single-positive thymocytes. Additionally, we found high levels of HERV mRNAs in TECs. Overall, our data support a tight regulation of HERV expression during human T cell development, with possible implications for the process of T cell selection.

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Expression of APOBEC family members as regulators of endogenous retroelements and malignant transformation in systemic autoimmunity

Cited by 12 publications

References 60 publications

APOBECs orchestrate genomic and epigenomic editing across health and disease

APOBECs orchestrate genomic and epigenomic editing across health and disease

Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus

Expression of Human Endogenous Retroviruses in the Human Thymus Along T Cell Development

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