March 24th, 2024
Recent Publications Harnessing the Power of Translatomics.
Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.
In this week’s Sunday papers, Huang et al. show how ribo-seq helped identify cryptic immunopeptides expressed from a circular RNA. Wang et al. used that polysome profiling to reveal that miRNA-targeted mRNAs are associated with lighter polysome fractions. Zhong et al. underlined that circNFIB suppressed the synthesis of arachidonic acid that is associated with tumorigenesis and metastasis.
Tumour circular RNAs elicit anti-tumour immunity by encoding cryptic peptides
Nature, 2024
Huang, D., Zhu, X., Ye, S., Zhang, J., Liao, J., Zhang, N., Zeng, X., Wang, J., Yang, B., Zhang, Y., Lao, L., Chen, J., Xin, M., Nie, Y., Saw, P.E., Su, S. and Song, E.
With the goal of identifying tumour-specific cryptic peptides that might stimulate adaptive immunity, Huang et al. used mass spectrometry of the HLA class I (HLA-I) peptidome coupled with ribosome profiling of human breast cancer samples. The prediction of noncanonical translation by ribosome profiling greatly reduced the sequence search-space for cryptic peptides. With this approach they identified several HLA-I-binding cryptic antigenic peptides that are expressed from a tumour-specific circular RNA (circRNA): circFAM53B. These cryptic peptides efficiently primed naive CD4+ and CD8+ T cells in an antigen-specific manner and induced anti-tumour immunity. Clinically, the expression of circFAM53B and its encoded peptides was associated with substantial infiltration of antigen-specific CD8+ T cells and better survival in patients with breast cancer and patients with melanoma. Mechanistically, circFAM53B-encoded peptides had strong binding affinity to both HLA-I and HLA-II molecules. In vivo, administration of vaccines consisting of tumour-specific circRNA or its encoded peptides in mice bearing breast cancer tumours or melanoma induced enhanced infiltration of tumour-antigen- specific cytotoxic T cells, which led to effective tumour control. Overall, these findings show that noncanonical translation of circRNAs can drive efficient anti-tumour immunity, which suggests that vaccination exploiting tumour-specific circRNAs may serve as an immunotherapeutic strategy against malignant tumours.
The Enrichment of miRNA-Targeted mRNAs in Translationally Less Active over More Active Polysomes
Biology, 2023
Wang, T., Tian, S., Tikhonova, E.B., Karamyshev, A.L., Wang, J.J., Zhang, F. and Wang, D.
Wang et al. investigated the translation state of miRNA-bound mRNAs using polysome profiling. Their approach involved the comparison of light (2-9 ribosomes per mRNA) and heavy (>9 ribosomes per mRNA) between a wild type HCT116 cell-line and its isogenic mutant from which mature miRNA production by DICER is disrupted (DICER1 KO). Although the length of the open reading frame is a major predictor of light- to heavy-polysome mRNA abundance ratios, Wang et al show that this is a less powerful predictor in wild type cells compared to DICER1 KO cells where a clear shift in miRNA-targeted mRNAs from light to heavy polysomes in mutant cells was evident. Curiously, Wang et al show that miRNAs tend to target mRNAs with longer ORFs.
Overall, Wang et al provide evidence for the light-polysome enrichment of miRNA-targeted mRNAs to reconcile polysome association and moderate translation inhibition, and that ORF length is an important, though currently under-appreciated, transcriptome regulation parameter.
circNFIB decreases synthesis of arachidonic acid and inhibits breast tumor growth and metastasis
European Journal of Pharmacology, 2024
This paper explores how circNFIB, a circular RNA, suppressed breast tumor growth and metastasis by reducing arachidonic acid synthesis. circNFIB achieved this by inhibiting the translation of key enzymes involved in arachidonic acid production.
Zhong et al searched for differential abundance of circRNAs in breast cancer tissue compared with adjacent normal tissues and identified 59 differentially expressed circRNAs in breast cancer tissues, including 47 up-regulated and 12 down-regulated. Among the 59 differentially expressed circRNAs, 5 were novel circRNAs which were not included in circBase. One of the down regulated circRNAs, circNFIB , was studied further. Overexpression of circNFIB in MDA-MB-231 and MCF-7 breast cancer cell-lines inhibited cell proliferation, colony formation and cell migration/invasion, whereas knockdown of circNFIB promoted cell proliferation and invasion. Furthermore, in vivo studies revealed that circNFIB inhibited tumour growth and metastasis in mice.
Interestingly, an ORF within circNFIB potentially encoding a 56 amino acid protein was identified. With a combination of ribosome profiling and epitope-tagging, Zhong et al provide evidence for translation of the circNFIB ORF.
Finally, a possible function for circNFIB was revealed by metabolomics analysis indicating that circNFIB may inhibit the synthesis of arachidonic acid by regulating phospholipase. The authors speculate that circNFIB may inhibit breast tumour growth and metastasis partly by inhibiting arachidonic acid.