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Abstract Background Transmissible cancers lie at the intersection of oncology and infectious disease, two traditionally divergent fields for which gene expression studies are particularly useful for identifying the molecular basis of phenotypic variation. In oncology, transcriptomics studies, which characterize the expression of thousands of genes, have identified processes leading to heterogeneity in cancer phenotypes and individual prognoses. More generally, transcriptomics studies of infectious diseases characterize interactions between host, pathogen, and environment to better predict population-level outcomes. Tasmanian devils have been impacted dramatically by a transmissible cancer (devil facial tumor disease; DFTD) that has led to widespread population declines. Despite initial predictions of extinction, populations have persisted at low levels, due in part to heterogeneity in host responses, particularly between sexes. However, the processes underlying this variation remain unknown. Results We sequenced transcriptomes from healthy and DFTD-infected devils, as well as DFTD tumors, to characterize host responses to DFTD infection, identify differing host-tumor molecular interactions between sexes, and investigate the extent to which tumor gene expression varies among host populations. We found minimal variation in gene expression of devil lip tissues, either with respect to DFTD infection status or sex. However, 4088 genes were differentially expressed in tumors among our sampling localities. Pathways that were up- or downregulated in DFTD tumors relative to normal tissues exhibited the same patterns of expression with greater intensity in tumors from localities that experienced DFTD for longer. No mRNA sequence variants were associated with expression variation. Conclusions Expression variation among localities may reflect morphological differences in tumors that alter ratios of normal-to-tumor cells within biopsies. Phenotypic variation in tumors may arise from environmental variation or differences in host immune response that were undetectable in lip biopsies, potentially reflecting variation in host-tumor coevolutionary relationships among sites that differ in the time since DFTD arrival.
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Expression of Human Endogenous Retroviruses in Systemic Lupus Erythematosus: Multiomic Integration With Gene Expression
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies predominantly to nuclear material. Many aspects of disease pathology are mediated by the deposition of nucleic acid containing immune complexes, which also induce the type 1interferon response, a characteristic feature of SLE. Notably, SLE is remarkably heterogeneous, with a variety of organs involved in different individuals, who also show variation in disease severity related to their ancestries. Here, we probed one potential contribution to disease heterogeneity as well as a possible source of immunoreactive nucleic acids by exploring the expression of human endogenous retroviruses (HERVs). We investigated the expression of HERVs in SLE and their potential relationship to SLE features and the expression of biochemical pathways, including the interferon gene signature (IGS). Towards this goal, we analyzed available and new RNA-Seq data from two independent whole blood studies using Telescope. We identified 481 locus specific HERV encoding regions that are differentially expressed between case and control individuals with only 14% overlap of differentially expressed HERVs between these two datasets. We identified significant differences between differentially expressed HERVs and non-differentially expressed HERVs between the two datasets. We also characterized the host differentially expressed genes and tested their association with the differentially expressed HERVs. We found that differentially expressed HERVs were significantly more physically proximal to host differentially expressed genes than non-differentially expressed HERVs. Finally, we capitalized on locus specific resolution of HERV mapping to identify key molecular pathways impacted by differential HERV expression in people with SLE.
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- Award ID(s):
- 2028280
- PAR ID:
- 10332914
- Date Published:
- Journal Name:
- Frontiers in Immunology
- Volume:
- 12
- ISSN:
- 1664-3224
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fimmu.2021.661437
