May 19th, 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, Dai et al. present a newly developed technique they call ultrafast bisulfite sequencing that can rapidly and accurately detect 5-methylcytosine modification in both DNA and RNA. Karousis et al. review how coronaviruses control viral and host translation during different stages of infection. Xue et al. show that METTL16, an RNA methyltransferase, methylates specific sites on pre-ribosomal RNA to increase mRNA translation for stemness-related proteins that sustains the self-renewal of liver cancer stem cells.

Ultrafast bisulfite sequencing detection of 5-methylcytosine in DNA and RNA

Nature Biotechnology, 2024

Nicholas Vrettos, Jan Oppelt, Ansgar Zoch, Paraskevi Sgourdou, Haruka Yoshida, Brian Song, Ryan Fink, Dónal O’Carroll and Zissimos MourelatosDai, Q., Ye, C., Irkliyenko, I., Wang, Y., Sun, H.L., Gao, Y., Liu, Y., Beadell, A., Perea, J., Goel, A. and He, C.

5-methylcytosine (5mC) modification plays a crucial role in gene regulation and has profound implications for various biological processes, such as development and disease. While conventional bisulfite sequencing (BS-seq) is capable of detecting 5mC, it does have its limitations, the two major ones being DNA/RNA degradation and suboptimal C-to-U conversion. In this paper, Dai et al. present a newly developed technique which they refer to as ultrafast BS-seq (UBS-seq), which addresses the limitations of the standard BS-seq. 

UBS-seq attempts to overcome the limitations of conventional BS-seq by using a higher concentration of bisulfite reagents and a higher reaction temperature. The authors reasoned that a higher concentration of reagents and higher reaction temperatures would lead to a more complete bisulfite reaction, with the latter also denaturing dsDNA or the secondary structures in RNA so that a complete bisulfite conversion could be accomplished. While the higher reagent concentration and reaction temperature would lead to more DNA/RNA degradation, the much shorter reaction time compensates for this leading to reduced degradation overall. 

The authors found that UBS-seq outperforms conventional BS-seq in several areas some of which are lower background noise, higher CpG coverage and less overestimation of 5mC fraction. In addition, UBS-seq also expanded the scope of analysis to include RNA modifications, which is a major issue in conventional BS-seq due to the high false-positive rates caused by incompletion C-to-U conversion. UBS-seq thus enables researchers to explore the dynamic roles of 5mC modifications in both DNA and RNA.

Overall, the numerous advantages that UBS-seq offers could significantly advance research in epigenetics and molecular biology, offering insights into epitranscriptomic modifications and shedding light on previously unexplored aspects of gene regulation and cellular processes.

Coronavirus takeover of host cell translation and intracellular antiviral response: a molecular perspective

The EMBO Journal, 2024

Karousis, E.D., Schubert, K. and Ban, N.

Coronaviruses are RNA viruses that cause respiratory illnesses in humans and animals. Understanding how these viruses control RNA translation in host cells is key to developing antiviral treatments. In this review Karousis et al. provide an overview of how coronaviruses control viral and host translation during different stages of infection and compares these strategies to those of other RNA viruses.

The authors first discuss the mechanisms by which coronaviruses modulate host cell translation, summarizing the different ways in which coronaviruses trigger stress response mechanisms, such as via activation of protein kinase R (PKR) or via the unfolded protein response. They also cover how host cell protein synthesis can be suppressed by viral proteins, such as nonstructural protein 1 (Nsp1). Nsp1 disrupts the host mRNA translation by binding to the ribosome and inducing mRNA degradation, and hence, favouring the translation of viral mRNAs over cellular mRNAs.

The authors also delve into the unique features of Cov-encoded RNA’s. They cover the structural features of coronaviruses, RNA editing of viral genomes via mammalian enzymes, interaction with poly-A binding proteins and cap-dependent translation initiation. In addition, they cover programmed ribosomal frameshifting (PRF) and how ribosome profiling  and cryo-EM experiments were used to elucidate the molecular mechanism of PRF in SARS-CoV-2.

This comprehensive overview outlines the strategies that allow coronaviruses to replicate efficiently and establish robust infections. However, the authors note that additional features of coronaviral RNAs not covered in depth in this review are likely to play a role during their translation in infected cells, for example, leaky scanning and uORFs.

METTL16 promotes liver cancer stem cell self-renewal via controlling ribosome biogenesis and mRNA translation

Journal of Hematology & Oncology, 2024

Xue, M., Dong, L., Zhang, H., Li, Y., Qiu, K., Zhao, Z., Gao, M., Han, L., Chan, A.K., Li, W., Leung, K., Wang, K., Pokharel, S. P., Qing, Y., Liu, W., Wang, X., Ren, L., Bi, H., Yang, L., Shen, C., Chen, Z., Melstrom, L., Li, H., Timchenko, N., Deng, X., Huang, W., Rosen, S.T., Tian, J., Xu, L., Diao, J., Chen, C., Chen, J., Shen, B., Chen, H. and Su, R.


Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fourth leading cause of cancer-related deaths worldwide. It’s high rate of recurrence and heterogeneity make finding an effective treatment challenging. Emerging evidence suggests cancer stem cells (CSCs) play an important role in the development, progression, and recurrence of HCC. A previous study by the same authors showed that Methyltransferase 16 (METTL16), an RNA N6-methyladenosine (m6A) methyltransferase, was the most essential gene for cancer cell survival in the METTL family.

In this study Xue et al. aim to explore the role of METTL16 in promoting HCC initiation, progression, and liver CSC self-renewal. They show that METTL16 regulates ribosome biogenesis by methylating specific sites on pre-ribosomal RNA, thereby promoting the assembly of functional ribosomes. This results in increased translation of mRNAs encoding stemness-related proteins, which sustains the self-renewal and tumorigenic properties of CSCs.

The authors also reveal an unexpected nucleolar localization of METTL16, which facilitates rRNA processing and ribosome biogenesis in a methyltransferase-dependent manner. METTL16 directly interacts with eIF3a/b to promote mRNA translation initiation and is crucial for promoting HCC growth and mRNA translation. The knockdown of METTL16 impaired CSC self-renewal capacity and tumour growth in mouse models of liver cancer.

METTL16-mediated translational initiation reprogrammed translational control in HCC to maintain tumour plasticity and CSC stemness. Ribosome profiling was used to identify specific mRNAs whose translation is enhanced by METTL16-mediated methylation, including those encoding stemness-related proteins critical for CSC maintenance. Overall, this study elucidated the METTL16 mechanisms in promoting liver CSC self-renewal, and thus, sheds light on the development of therapeutic strategies for liver cancer.

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