January 14th, 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, Xu et al. find evidence of widespread functional elements in unannotated sequences, Zhu et al. observe the role of exosome-delivered lncRNA in promoting cancer metastasis, and Iyyappan et al. explore the dynamics of translation in oocytes and early embryos. 

Evidence for widespread existence of functional novel and non-canonical human transcripts

BMC Biology , 2023

Xu, D., Tang, L., Zhou, J., Wang, F., Cao, H., Huang, Y. and Kapranov, P

Using a lentivirus-based insertional mutagenesis strategy, Xu et al. performed an unbiased forward genetics screen, looking into the unexplored functional elements of the human genome. The researchers investigated the phenotypic effects of insertions in essential protein-coding genes and long non-coding RNAs (lncRNAs) using an aneuploid cell line. Two analytical approaches, individual insertion events and region-based analysis, were applied to detect insertions affecting cellular fitness, revealing a significant depletion in essential genes. Intriguingly, most insertions causing phenotypic alterations were not associated with exons of known genes, but instead located in intergenic spaces, challenging assumptions about their indirect effects on gene expression. 

The study extended its focus beyond annotated genomic elements, exploring unannotated portions of the human genome. Phenotypic insertions were found to be enriched in unannotated exons that were predicted in silico by GENSCAN, suggesting the existence of a substantial pool of functional exons yet to be annotated. Further investigation revealed the inclusion of novel exons in response to anticancer drug treatments, hinting at a prevalence of alternative splicing events in stress-induced scenarios. Additionally, the study identified non-canonical transcripts, previously considered aberrant splicing products, as potential bi-cistronic messenger RNAs encoding two separate proteins. Using Ribo-seq, the authors find evidence of translation in 14% of GENSCAN predicted, unannotated intragenic exons. 

These findings challenge existing notions of transcript annotation and emphasize the need for systematic efforts to annotate in silico predicted exons, shedding light on the complex landscape of both protein-coding and non-coding transcripts in the human genome.

The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism

Cell Death and Disease, 2023

Zhu, K.G., Yang, J., Zhu, Y., Zhu, Q., Pan, W., Deng, S., He, Y., Zuo, D., Wang, P., Han, Y. and Zhang, H.Y.

This article investigates the role of exosome-delivered long non-coding RNA (lncRNA) in promoting lymph node metastasis (LNM) in gastric cancer. Gastric cancer is a prevalent malignancy globally, and LNM significantly influences prognosis. In this paper, Zhu et al. reveal that lncAKR1C2, found in serum exosomes of gastric cancer patients, is markedly upregulated in cases with LNM. High lncAKR1C2 levels are associated with shorter progression-free and overall survival.

 

Using Ribo-seq, the authors found lncAKR1C2 to be actively translated, identifying a microprotein, pep-AKR1C2, encoded by exosome-derived lncAKR1C2 in lymphatic endothelial cells. Functionally, pep-AKR1C2 was shown to enhance fatty acid oxidation (FAO) and ATP production in lymphatic endothelial cells by regulating the YAP-mediated expression of the essential FAO enzyme, carnitine palmitoyltransferase 1A (CPT1A). This in turn leads to increased lymphangiogenesis and LNM.

Metabolomic analysis indicated higher lipid metabolism in lymph node metastases compared to primary tumors, supporting the importance of FAO in LNM. In vivo experiments with mouse models of gastric cancer metastasis corroborated the role of exosomal lncAKR1C2 and its encoded microprotein in promoting lymphatic metastasis.

The study not only sheds light on the molecular mechanisms underlying LNM in gastric cancer but also introduces a novel concept of exosome-delivered lncRNA encoding functional microproteins. Targeting lncAKR1C2 may provide potential therapeutic avenues for inhibiting LNM in gastric cancer, presenting a valuable contribution to the understanding and potential treatment of this malignancy.

The translational oscillation in oocyte and early embryo development

Nucleic Acids Research, 2023

Iyyappan, R., Aleshkina, D., Ming, H., Dvoran, M., Kakavand, K., Jansova, D., Del Llano, E., Gahurova, L., Bruce, A.W., Masek, T. et al.

This article explores the intricate regulation of gene expression and protein synthesis during oocyte and early embryo development, focusing on the role of translational control in this dynamic process. The study investigates the changes in global translation during various stages of the cell cycle, with an emphasis on interphase and metaphase. The researchers employed methods such as 35S-Methionine incorporation assays and Scarce Sample Polysome Profiling to analyze the translational profiles of maternal mRNAs.

The findings indicate a significant decrease in global protein synthesis during metaphases (M-phases) of meiosis and the subsequent embryonic mitoses. The study reveals highly dynamic translational changes in oocytes and early embryos, with specific subsets of maternal mRNAs being actively translated during different cell cycle stages. The researchers identified 12 distinct clusters of mRNAs associated with polysomes, each exhibiting a specific pattern of translation related to particular developmental stages.

The study also delves into the activation patterns of key translational regulators, including eukaryotic initiation factor 4E (eIF4E), eukaryotic elongation factor 2 (eEF2), and mammalian target of rapamycin (mTOR), during M-phases. The results show a uniform activation of these factors during M-phases across all developmental stages, indicating a coordinated and stage-specific regulation of translation.

Furthermore, the researchers explored the impact of inhibiting the eEF2 kinase (eEF2K)/eEF2 axis on oocyte meiotic and embryo developmental competence. This inhibition negatively affected the preimplantation developmental potential of oocytes and zygotes, highlighting the crucial role of translation elongation during early development.

The authors provide valuable insights into the temporal regulation of mRNA translation during oocyte and early embryo development, emphasizing the importance of translational control in orchestrating the intricate processes of cell cycle progression and embryogenesis.

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