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

Abstract

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.

Keywords: LIN28B; Onco-exaptation; Placental Development; Transposable Elements (TEs).

Fig. 1

Expression of six onco-exaptation candidates in placental and somatic tissue. TE expression is plotted on the left Y axis and gene expression is plotted on the right axis. Placenta n = 30, somatic n = 8 (brain, heart, kidney, liver, lung, ovary, testis and melanocyte)

Fig. 2

Expression of onco-exaptation candidates in first trimester and term placental tissue. TE expression is plotted on the left Y axis and gene expression is plotted on the right axis. First trimester placenta n = 14, term placenta n = 16

Fig. 3

Expression of onco-exaptation candidates in hESC and somatic tissues. TE expression is plotted on the left Y axis and gene expression is plotted on the right axis. hESC n = 8, somatic n = 8 (brain, heart, kidney, liver, lung, ovary, testis and melanocyte)

Fig. 4

RNA-Seq expression quantification of LIN28B. A LIN28B locus with the AluSINE elements, amplicons for methylation analysis and rt-qPCR primers annotated. B Expression of the AluJbSINE/TE element that functions as an alternate promotor for LIN28B. Placenta First (First Trimester) n = 14, Placenta Term n = 8, TSC (trophoblast stem cell) n = 9, Somatic n = 8 (brain, heart, kidney, liver, lung, ovary, testis and melanocyte). ****P value < 0.0001(T test) B. Expression of LIN28B gene quantified by Stringtie. Placenta First Trimester n = 14, Placenta Term n = 8, Somatic n = 8 (brain, heart, kidney, liver, lung, ovary, testis and melanocyte). ****P value < 0.0001, ***P value 0.0001–0.001 (2 way ANOVA)

Fig. 5

Quantification of expression of the TE-derived LIN28B transcript by RT-qPCR and RNA-Sequencing. A Expression of the TE-derived LIN28B transcript in first trimester placental tissues and somatic tissues quantified by RNA-Seq (placenta n = 14 (first trimester), somatic n = 9). B Expression of the TE-derived LIN28B transcript in first trimester placental tissue samples and somatic tissues as quantified by RT-qPCR. (placenta n = 7, somatic n = 3) ****P value < 0.0001, *P value 0.01–0.05 (Mann–Whitney test)

Fig. 6

DNA methylation analysis results for LIN28B. A Mean CpG methylation for the canonical promoter of LIN28B (*P value = 0.0470—Kruskal–Wallis test) B Methylation of each CpG within the canonical LIN28B promoter amplicon. C. Mean CpG methylation for the TE-derived promoter of LIN28B (*P value = 0.0128—Kruskal–Wallis test). D. Methylation of each CpG within the TE-derived promoter of LIN28B. (Error bars represent SD, minimum read depth of 80). Placenta first trimester n = 14, somatic n = 2