COMPARATIVE EXPRESSION ANALYSIS OF HUMAN ENDOGENOUS RETROVIRUS ELEMENTS IN PERIPHERAL BLOOD OF CHILDREN WITH SPECIFIC LANGUAGE IMPAIRMENT
Minchev DS1,2,*, Popov NT3, Naimov SI1, Minkov IN4, Vachev TI1
*Corresponding Author: Assistant Professor Danail S. Minchev, Department of Medical Biology, Faculty of Medicine, Medical University-Plovdiv, 4000, Plovdiv, Bulgaria. Tel: +359-896-313-627. E-mail: dante17@abv.bg
page: 49

DISCUSSION

To date, there have been no published data on HERV expression in the context of the SLI condition. To the best of our knowledge, this is the first cohort study to announce differences in transcript abundance of specific HERV genes in the blood of children with SLI compared with a control group. We have studied HERV transcript levels in peripheral blood of children with SLI. Throughout our study we have analyzed the expression pattern of five different HERV loci: HERV-K (HLM-2) gag, HERV-K env, HERV-W pol, HERV-P env and HERV-R env. All of the five genes studied appeared to be ubiquitously expressed in the peripheral blood of children in both the SLI and control groups. Two of these, HERV-K (HLM-2) gag and HERV-P env, appeared to be differentially expressed between the two groups. Despite the growing evidence of a strong genetic basis for SLI during the last decade, the precise genetic mechanisms of SLI remain elusive. Many researchers suggest that SLI is a multi causation condition with both genetic and environmental factors involved. Numerous molecular studies have established a set of SLI-associated genes whose single nucleotide polymorphism (SNP) profile or differential expression is of particular importance for SLI development [20]. Despite this large amount of research effort, no assessment of the HERV expression has been made in the aforementioned studies. In some cases, HERV regulatory regions and HERV encoded products may play an important role in essential physiological processes. For example, syncytin-1 and syncytin-2 proteins that mediate trophoblast cell fusion during placental development, derive from HERV Envelope proteins. In a recent study, Bhat et al. [21] revealed that HERV-K Env is able to promote a considerable neuroprotective effect in a case of HIV infection. According to Thompson et al. [22], and Sundaram et al. [23], about 20.0% of all functionally active transcription factor binding sites in human and murine genomes are LTR-related. We observed relevant changes in gene expression in terms of a small but statistically significant reduction in HERV-K (HLM-2) gag (1.41-fold) and HERV-P env (1.67- fold) transcript levels. The HERV downregulation presumes an active suppression of these elements. As HERV expression is modulated by various mechanisms, the differential gene expression we observed is probably a result of many factors affecting HERV regulation. Regulation mechanisms of particular importance involve DNA methylation and several trans-acting transcription factors [24]. Generally, transcription of active HERV loci is mediated by a 5’- LTR core promoter able to support transcription at a basal level. Transcription is negatively regulated mainly by CpG methylation at the 5’-LTR. According to Wentzensen et al. [25], the expression of a specific member of the HERV-H in gastrointestinal cancer cells correlates with demethylation of the 5’-LTR. The presence of enhancer sequences within the 5’-LTRs has also been demonstrated. In addition, several trans-acting transcriptional factors, which bind to HERV promoters and en-hancers, have been identified: YY1, Sp-1, Oct-1, GATA, GCM1 [24,26-28] Nevertheless, our RNA-seq data from a previous expression study on pooled SLI and ASD samples [29] suggests no changes in the expression levels of the aforementioned transcription factors and the most DNA-methyltransferases. On this basis, we can speculate that the observed differences in the HERV transcript levels can be due to negligibly small but specific changes in various gene regulation processes. Further efforts are still needed for a complete characterization of HERV regulation. The most important findings in our study were that HERV expression levels in blood correlate negatively with the SLI development and may specifically discriminate SLI patients from healthy controls. The expression profile we obtained may be useful for the investigation of many diseases of the central nervous system that are suspected to be associated with the retroviral activity. While the patient cohort was very well characterized and representative for an SLI population, the total number of participants was not large enough to definitively create a model for prediction of SLI or characterize HERV expression differences that may be more highly associated with SLI subtypes. Due to the small sample size, analysis of the data with respect to medication, sex, special diet, race, ethnicity or other potential confounding covariates, was not conclusive. Our findings are in agreement with several other studies in which HERV downregulation has been clearly established [30-33]. Alterations in HERV expression occur in various pathological conditions, in a wide variety of cancer conditions, in inflammation reactions, and in autoimmunity [30-33]. While a remarkable number of studies support the overexpression of HERVs in various complex conditions, our findings are entirely coherent with those in which significantly lower expression levels of specific HERV loci has also been reported [30-36]. In spite of the fact that a vast majority of human endogenous retrovirus elements are upregulated in malignant cells, in a very few cancer cases, their expression is suppressed. Syncytin-1 is described to be underexpressed in several tumor types, which suggest its potential beneficial effect. Syncytin-1 has been shown to be downregulated in pancreatic adenocarcinomas, while its stable expression in a melanoma cell line correlates with restricted cell growth [30]. Liang et al. [31] evaluated transcription of the HERVrelated gene psiTPTE22-HERV in kidney, liver, lung, and stomach tumors in comparison with normal tissue samples. The authors prove that psiTPTE22-HERV transcripts were notably lower in all tumor tissues examined. Their results confirm that the expression of the HERV-related gene is suppressed solely in the cancer samples and that this suppression correlates with the malignancy of the cells [31]. According to Kowalczyk et al. [32], HERV-W env expression in peripheral blood mononuclear cell (PBMC) samples from patients with localized scleroderma, negatively correlates with the severity of the disease. Moreover, HERV-W env levels in skin samples from the patients were distinctively lower, compared to those in the control group samples [32]. Lattekivi et al. [33] performed a differential expression study of HERVs in psoriasis at a whole transcriptome level. The authors observed high expression of repetitive elements in both patients and healthy controls. Most of the endogenous retrovirus loci with significant changes in expression between the two studied groups appeared to be downregulated in psoriasis skin. The authors set a differential expression fold change thresholds at 0.71 and 1.41 and a false discovery rate at <0.01. They discovered downregulation of 17 HERV families in lesional and three HERV families in non-lesional psoriatic skin in comparison with healthy skin. Their findings clearly demonstrated the global repression of the endogenous retrovirus elements in psoriatic skin. The HERV downregulation has also been confirmed in psoriasis by Gupta et al. [34]. Weis et al. [35] discovered a substantial reduction in the HERV-W gag gene expression levels in brain samples from patients with schizophrenia and bipolar disorder. Along with a noticeable overexpression of HERV-H, Balestrieri et al. [36] discovered downregulation of HERV-W in peripheral blood samples of children with autistic spectrum disorder. In contrast to HERV-H, HERV-W was found to be downregulated in the autistic group compared to the healthy controls (with less than a 2-fold change). These results clearly suggest that HERV transcript levels can specifically characterize a complex psychiatric condition such as autism and serve as putative molecular markers for it. It is noteworthy to mention that despite the small absolute change, the reported HERV-W downregulation is still considered important in terms of statistical significance. Our results together with the vast scientific data obtained by other research groups support that HERV genes play an important role in normal cell processes. Human endogenous retroviruses are not only “junk” or “selfish” DNA, but also the key factors and markers for many pathological conditions. Further clarification of the molecular mechanisms and pathways in which HERVs participate is needed for a complete understanding of their functions in norm and pathology. In general, despite the huge body of evidence supporting overexpression of HERVs in many diseases, pathologies with significantly lower expression levels of HERVs have also been reported [30-36]. In this context, our study presents evidence of minor (>1.4-fold), but statistically reliable downregulation of two HERV-encoded genes. Our finding is consistent with previous studies in which low HERV expression has been described. Of particular interest is the fact that differential expression of HERV-K (HML-2) gag and HERV-P env is a sensitive marker that can discriminate children with SLI from healthy controls.



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