The transposable element-derived transcript of LIN28B has a placental origin and is not specific to tumours.

Transposable elements (TEs) are genetic elements that have evolved as crucial regulators of human development and cancer, functioning as both genes and regulatory elements. When TEs become dysregulated in cancer cells, they can serve as alternate promoters to activate oncogenes, a process known as onco-exaptation. This study aimed to explore the expression and epigenetic regulation of onco-exaptation events in early human developmental tissues. We discovered co-expression of some TEs and oncogenes in human embryonic stem cells and first trimester and term placental tissues. Previous studies identified onco-exaptation events in various cancer types, including an AluJb SINE element-LIN28B interaction in lung cancer cells, and showed that the TE-derived LIN28B transcript is associated with poor patient prognosis in hepatocellular carcinoma. This study further characterized the AluJb-LIN28B transcript and confirmed that its expression is restricted to the placenta. Targeted DNA methylation analysis revealed differential methylation of the two LIN28B promoters between placenta and healthy somatic tissues, indicating that some TE-oncogene interactions are not cancer-specific but arise from the epigenetic reactivation of developmental TE-derived regulatory events. In conclusion, our findings provide evidence that some TE-oncogene interactions are not limited to cancer and may originate from the epigenetic reactivation of TE-derived regulatory events that are involved in early development. These insights broaden our understanding of the role of TEs in gene regulation and suggest the potential importance of targeting TEs in cancer therapy beyond their conventional use as cancer-specific markers.

Unveiling the hidden players: The crucial role of transposable elements in the placenta and their potential contribution to pre-eclampsia.

The human placenta is a vital connection between maternal and fetal tissues, allowing for the exchange of molecules and modulation of immune interactions during pregnancy. Interestingly, some of the placenta's unique functions can be attributed to transposable elements (TEs), which are DNA sequences that have mobilised into the genome. Co-option throughout mammalian evolution has led to the generation of TE-derived regulators and TE-derived genes, some of which are expressed in the placenta but silenced in somatic tissues. TE genes encompass both TE-derived genes with a repeat element in the coding region and TE-derived regulatory regions such as alternative promoters and enhancers. Placental-specific TE genes are known to contribute to the placenta's unique functions, and interestingly, they are also expressed in some cancers and share similar functions. There is evidence to support that aberrant activity of TE genes may contribute to placental pathologies, cancer and autoimmunity. In this review, we highlight the crucial roles of TE genes in placental function, and how their dysregulation may lead to pre-eclampsia, a common and dangerous placental condition. We provide a summary of the functional TE genes in the placenta to offer insight into their significance in normal and abnormal human development. Ultimately, this review highlights an opportunity for future research to investigate the potential dysregulation of TE genes in the development of placental pathologies such as pre-eclampsia. Further understanding of TE genes and their role in the placenta could lead to significant improvements in maternal and fetal health.

Can Immune Suppression and Epigenome Regulation in Placenta Offer Novel Insights into Cancer Immune Evasion and Immunotherapy Resistance?

Cancer is the second leading cause of mortality and morbidity in the developed world. Cancer progression involves genetic and epigenetic alterations, accompanied by aggressive changes, such as increased immune evasion, onset of metastasis, and drug resistance. Similar to cancer, DNA hypomethylation, immune suppression, and invasive cell behaviours are also observed in the human placenta. Mechanisms that lead to the acquisition of invasive behaviour, immune evasion, and drug and immunotherapy resistance are presently under intense investigations to improve patient outcomes. Here, we review current knowledge regarding the similarities between immune suppression and epigenome regulation, including the expression of repetitive elements (REs), endogenous retroviruses (ERVs) and transposable elements (TEs) in cells of the placenta and in cancer, which are associated with changes in immune regulation and invasiveness. We explore whether immune suppression and epigenome regulation in placenta offers novel insights into immunotherapy resistance in cancer, and we also discuss the implications and the knowledge gaps relevant to these findings, which are rapidly being accrued in these quite disparate research fields. Finally, we discuss potential linkages between TE, ERV and RE activation and expression, regarding mechanisms of immune regulation in placenta and cancer. A greater understanding of the role of immune suppression and associated epigenome regulation in placenta could help to elucidate some comparable mechanisms operating in cancer, and identify potential new therapeutic targets for treating cancer.

RepExpress: A Novel Pipeline for the Quantification and Characterization of Transposable Element Expression from RNA-seq Data.

Transposable elements (TEs) are key regulators of both development and disease; however, their repetitive nature presents substantial computational challenges to their analysis. Due to a lack of computational tools and suitable analysis frameworks, TE expression is often not quantified at the locus level. Therefore, we have developed RepExpress, a novel pipeline that enables locus-level TE quantification and characterization. RepExpress enables the characterization of TE expression in a genomic context, and is the first tool focusing on the identification of tissue-specific TE-derived and TE-regulated genes. RepExpress identifies expressed TEs overlapping with annotated genomic features and enables tissue-specific profiles of TE-derived genes. TEs that are expressed with no overlap with any known genomic features are characterized by the closest downstream genomic feature enabling identification of novel TE-gene regulatory relationships. RepExpress takes standard RNA-seq data as input and performs genomic alignment optimized for TEs. Our novel pipeline quantifies expression of both TEs and genes using featureCounts and Stringtie, respectively. RepExpress then filters expressed repeats and characterizes their genomic context, enabling the identification of TEs that overlap with genes, or that may be influencing gene expression. Here, we describe RepExpress, and provide a step-by-step protocol detailing its workflow. We also discuss other TE analysis tools and their applicability to addressing different biological questions. © 2021 Wiley Periodicals LLC. Basic Protocol: RepExpress workflow.

Reawakening the Developmental Origins of Cancer Through Transposable Elements.

Transposable elements (TEs) have an established role as important regulators of early human development, functioning as tissue-specific genes and regulatory elements. Functional TEs are highly active during early development, and interact with important developmental genes, some of which also function as oncogenes. Dedifferentiation is a hallmark of cancer, and is characterized by genetic and epigenetic changes that enable proliferation, self-renewal and a metabolism reminiscent of embryonic stem cells. There is also compelling evidence suggesting that the path to dedifferentiation in cancer can contribute to invasion and metastasis. TEs are frequently expressed in cancer, and recent work has identified a newly proposed mechanism involving extensive recruitment of TE-derived promoters to drive expression of oncogenes and subsequently promote oncogenesis-a process termed onco-exaptation. However, the mechanism by which this phenomenon occurs, and the extent to which it contributes to oncogenesis remains unknown. Initial hypotheses have proposed that onco-exaptation events are cancer-specific and arise randomly due to the dysregulated and hypomethylated state of cancer cells and abundance of TEs across the genome. However, we suspect that exaptation-like events may not just arise due to chance activation of novel regulatory relationships as proposed previously, but as a result of the reestablishment of early developmental regulatory relationships. Dedifferentiation in cancer is well-documented, along with expression of TEs. The known interactions between TEs and pluripotency factors such as NANOG and OCTt4 during early development, along with the expression of some placental-specific TE-derived transcripts in cancer support a possible link between TEs and dedifferentiation of tumor cells. Thus, we hypothesize that onco-exaptation events can be associated with the epigenetic reawakening of early developmental TEs to regulate expression of oncogenes and promote oncogenesis. We also suspect that activation of these early developmental regulatory TEs may promote dedifferentiation, although at this stage it is hard to predict whether TE activation is one of the initial drivers of dedifferentiation. We expect that developmental TE activation occurs as a result of the establishment of an epigenetic landscape in cancer that resembles that of early development and that developmental TE activation may also enable cancers to exploit early developmental pathways, repurposing them to promote malignancy.