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Project description:Speckled Protein 140 (SP140) is a chromatin reader with critical roles regulating immune cell transcriptional programs, and SP140 splice variants are associated with immune diseases including Crohn’s disease, multiple sclerosis, and chronic lymphocytic leukemia. SP140 expression is currently thought to be restricted to immune cells. However, by analyzing human transcriptomic datasets from a wide range of normal and cancer cell types, we found recurrent cancer-specific expression of SP140, driven by an alternative intronic promoter derived from an intronic endogenous retrovirus (ERV). The ERV belongs to the primate-specific LTR8B family. The ERV drives expression of multiple cancer-specific isoforms, including a nearly full-length isoform that retains all the functional domains of the full-length canonical isoform and is also localized within the nucleus, consistent with a role in chromatin regulation. In a fibrosarcoma cell line, silencing the cancer-specific ERV promoter of SP140 resulted in increased sensitivity to interferon-mediated cytotoxicity and dysregulation of multiple genes. Our findings implicate aberrant ERV-mediated SP140 expression as a novel mechanism contributing to immune gene dysregulation in a wide range of cancer cells.
2024-02-20 | GSE256010 | GEO
Project description:Speckled Protein 140 (SP140) is a chromatin reader with critical roles regulating immune cell transcriptional programs, and SP140 splice variants are associated with immune diseases including Crohn’s disease, multiple sclerosis, and chronic lymphocytic leukemia. SP140 expression is currently thought to be restricted to immune cells. However, by analyzing human transcriptomic datasets from a wide range of normal and cancer cell types, we found recurrent cancer-specific expression of SP140, driven by an alternative intronic promoter derived from an intronic endogenous retrovirus (ERV). The ERV belongs to the primate-specific LTR8B family. The ERV drives expression of multiple cancer-specific isoforms, including a nearly full-length isoform that retains all the functional domains of the full-length canonical isoform and is also localized within the nucleus, consistent with a role in chromatin regulation. In a fibrosarcoma cell line, silencing the cancer-specific ERV promoter of SP140 resulted in increased sensitivity to interferon-mediated cytotoxicity and dysregulation of multiple genes. Our findings implicate aberrant ERV-mediated SP140 expression as a novel mechanism contributing to immune gene dysregulation in a wide range of cancer cells.
2024-02-20 | GSE256003 | GEO
Project description:An endogenous retrovirus regulates tumor-specific expression of the immune transcriptional regulator SP140
| PRJNA1077377 | ENA
Project description:An endogenous retrovirus regulates tumor-specific expression of the immune transcriptional regulator SP140 [RNA-seq]
| PRJNA1077371 | ENA
Project description:An endogenous retrovirus regulates tumor-specific expression of the immune transcriptional regulator SP140 [CUT&RUN]
| PRJNA1077383 | ENA
Project description:Retrovirus-like sequences account for 8 to 9% of the human genome. Among these sequences, about 8,000 pol-containing proviral elements have been identified to date. As part of our ongoing search for active and possibly disease-relevant human endogenous retroviruses (HERVs), we have recently developed an oligonucleotide-based microarray. The assay allows for both the detection and the identification of most known retroviral reverse transcriptase (RT)-related nucleic acids in biological samples. In the present study, we have investigated the transcriptional activity of representative members of 20 HERV families in 19 different normal human tissues. Qualitative evaluation of chip hybridization signals and quantitative analysis by real-time RT-PCR revealed distinct HERV activity in the human tissues under investigation, suggesting that HERV elements are active in human cells in a tissue-specific manner. Most active members of HERV families were found in mRNA prepared from skin, thyroid gland, placenta, and tissues of reproductive organs. In contrast, only few active HERVs were detectable in muscle cells. Human tissues that lack HERV transcription could not be found, confirming that human endogenous retroviruses are permanent components of the human transcriptome. Distinct activity patterns may reflect the characteristics of the regulatory machinery in these cells, e.g., cell type-dependent occurrence of transcriptional regulatory factors.
| S-EPMC538696 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-04-13 | GSE145616 | GEO
Project description:A significant proportion of the human genome consists of stably inherited retroviral sequences. Most human endogenous retroviruses (HERVs) became defective over time. The HERV-K(HML-2) family is exceptional because of its coding capacity and the possible involvement in germ cell tumor (GCT) development. HERV-K(HML-2) transcription is strongly upregulated in GCTs. However, regulation of HERV-K(HML-2) transcription remains poorly understood. We investigated in detail the role of CpG methylation on the transcriptional activity of HERV-K(HML-2) long terminal repeats (LTRs). We find that CpG sites in various HERV-K(HML-2) proviral 5' LTRs are methylated at different levels in the cell line Tera-1. Methylation levels correlate with previously observed transcriptional activities of these proviruses. CpG-mediated silencing of HERV-K(HML-2) LTRs is further corroborated by transcriptional inactivity of in vitro-methylated 5' LTR reporter plasmids. However, CpG methylation levels do not solely regulate HERV-K(HML-2) 5' LTR activity, as evidenced by different LTR activities in the cell line T47D. A significant number of mutated CpG sites in evolutionary old HERV-K(HML-2) 5' LTRs suggests that CpG methylation had already silenced HERV-K(HML-2) proviruses millions of years ago. Direct silencing of HERV-K(HML-2) expression by CpG methylation enlightens upregulated HERV-K(HML-2) expression in usually hypomethylated GCT tissue.
| S-EPMC538560 | biostudies-literature
Project description:Recent evidence indicates that human cancer cells reactivate the expression of latent human endogenous retroviral (HERV) proteins. However, the extent to which cancer patients mount de novo immune responses against expressed HERV elements is unclear. In this study, we determined the extent of HERV-K env expression in human breast cancer (BC) and whether both humoral and cell-mediated immunity against HERV-K can be found in BC patients. We found HERV-K env protein expression in 88% of BC (n = 119) but not in normal breast (n = 76) tissues. ELISA screening assays detected significant titers of anti-HERV-K env IgG in a large proportion of BC patients. T-cell responses against HERV-K were also detected in peripheral blood mononuclear cells (PBMC) from BC patients stimulated with autologous dendritic cells pulsed with HERV-K env SU antigens. These responses included induction of T-cell proliferation (P = 0.0043), IFN-gamma production measured by enzyme-linked immunospot (P < 0.0001), and multiplex cytokine secretion (P = 0.0033). Multiplex cytokine analysis found a T-helper 1 cytokine response, including interleukin (IL)-2 (P = 0.0109), IL-6 (P = 0.0396), IL-8 (P = 0.0169), and IP-10 (P = 0.0045) secretion during in vitro stimulation of BC PBMC with HERV-K antigen. We also found HERV-K-specific CTLs that were capable of lysing target cells expressing HERV-K env protein in BC patients but not in normal female controls without cancer. These findings suggest that retroviral gene products are capable of acting as tumor-associated antigens activating both T-cell and B-cell responses in BC patients.
| S-EPMC5802396 | biostudies-literature
Project description:Transposable elements (TEs) comprise approximately half of the human genome, and several independent lines of investigation have demonstrated their role in rewiring gene expression during development, evolution, and oncogenesis. The identification of their regulatory effects has largely been idiosyncratic, by linking activity with isolated genes. Their distribution throughout the genome raises critical questions-do these elements contribute to broad tissue- and lineage-specific regulation? If so, in what manner, as enhancers, promoters, RNAs? Here, we devise a novel approach to systematically dissect the genome-wide consequences of TE insertion on gene expression, and test the hypothesis that classes of endogenous retrovirus long terminal repeats (LTRs) exert tissue-specific regulation of adjacent genes. Using correlation of expression patterns across 18 tissue types, we reveal the tissue-specific uncoupling of gene expression due to 62 different LTR classes. These patterns are specific to the retroviral insertion, as the same genes in species without the LTRs do not exhibit the same effect. Although the LTRs can be transcribed themselves, the most highly transcribed TEs do not have the largest effects on adjacent regulation of coding genes, suggesting they function predominantly as enhancers. Moreover, the tissue-specific patterns of gene expression that are detected by our method arise from a limited number of genes, rather than as a general consequence of LTR integration. These findings identify basic principles of co-opting LTRs for genome evolution, and support the utility of our method for the analysis of TE, or other specific gene sets, in relation to the rest of the genome.
| S-EPMC4419796 | biostudies-literature