
October 27th, 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, the researchers used ribo-seq and polysome profiling techniques to address m6A modifications. Wang et al. investigated how methyltransferase-like-3 drove metabolic reprogramming to mediate m6A modifications for the regulation of cellular aging. Cai et al. showed that the modification enhanced the translation efficiency and stability of ZEB2 mRNA, leading to the accelerated renal fibrotic process. Chen et al. indicated that the modification was crucial in enhancing disease resistance in plants by improving the mRNA stability and regulating the expression of defence genes.
METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence
Nature Communications, 2024
Wang, C., Tanizawa, H., Hill, C., Havas, A., Zhang, Q., Liao, L., Hao, X., Lei, X., Wang, L., Nie, H., Qi, Y., Tian, B., Gardini, A., Kossenkov, A.V., Goldman, A., Berger, S.L., Noma, K., Adams, P.D. and Zhang, R.
The methyltransferase-like-3 (METTL3) is a catalytic RNA methyltransferase that constitutes one of the core subunits of methyltransferase complex (MTC). It mediates RNA N6-methyladenosine (m6A) modification. The study presented METTL3’s role as a crucial regulator in cellular senescence, which is a stress response, through the formation of stress granules (SGs).
The authors found that during senescence, METTL3 drove metabolic reprogramming by enhancing the expression of genes that regulated metabolic processes, leading to the accumulation of metabolites that are necessary for SG phase separation. This phase separation was essential for the proper function of SGs, which protected cells from stress-induced damage. Polysome profiling revealed that during cellular senescence, there was a significant shift in the translation landscape. This shift was influenced by METTL3, which affected the ribosome association of specific mRNAs.
The profiling identified that specific genes involved in metabolism and SG phase separation are preferentially translated in a METTL3-dependent manner during senescence. This selective translation supports the metabolic changes and SG dynamics observed in senescent cells. By promoting the translation of SG-related mRNAs, METTL3 ensures the proper formation and function of SGs, which are vital for protecting cells from stress during senescence.
By identifying METTL3 as a key regulator of senescence through its role in chromatin organization, gene expression, and translation, the findings highlighted the link between chromatin architecture, metabolism, and stress response during cellular aging, offering potential insights into age-related diseases and therapeutic approaches.
N6-methyladenosine triggers renal fibrosis via enhancing translation and stability of ZEB2 mRNA
Journal of Biological Chemistry, 2024
Cai, Y., Zhou, J., Xu, A., Huang, J., Zhang, H., Xie, G., Zhong, K., Wu, Y., Ye, P., Wang, H. and Niu, H.
Renal fibrosis (RF) is a progressive condition that can lead to chronic kidney disease (CKD). The study specifically focused on the role of N6-methyladenosine (m6A), a prevalent post-transcriptional modification of RNA, in regulating gene expression during RF. RF involves the excessive deposition of extracellular matrix proteins, leading to scarring and loss of kidney function. A key factor in this process is the epithelial-to-mesenchymal transition (EMT), in which epithelial cells acquire a more fibrotic phenotype. One of the critical regulators of EMT is ZEB2 (Zinc Finger E-box Binding Homeobox 2), a transcription factor that promotes fibrosis when upregulated.
This paper focuses on the role of m6A, a common RNA modification, in the development of RF. m6A levels are elevated in RF, a condition characterized by the excessive accumulation of extracellular matrix in the kidneys leading to chronic kidney disease. m6A modification enhanced the translation efficiency and stability of ZEB2 mRNA, leading to increased ZEB2 protein levels. This accelerated the fibrotic process.
Ribosome profiling analysis identified that m6A modification also impacted the translation of other fibrosis-associated genes. Pharmacological inhibition of m6A reduced ribosome association with ZEB2 mRNA, which led to a decrease in ZEB2 protein levels. This indicated that m6A methylation is crucial for the enhanced ribosome binding and translation of ZEB2. Polysome profiling revealed that m6A modification significantly increased the association of ZEB2 mRNA with polysomes, which are indicative of high translation activity. When m6A levels were reduced, ZEB2 mRNA distribution shifted back to lighter fractions, indicating decreased polysome association and reduced translation efficiency.
The research establishes a critical link between m6A RNA modification and RF, identifying ZEB2 mRNA as a key target. The findings highlight the potential of targeting m6A machinery as a novel therapeutic strategy to treat RF.
m⁶A modification plays an integral role in mRNA stability and translation during pattern-triggered immunity
Proceedings of the National Academy of Sciences, 2024
Chen, T., Greene, G.H., Motley, J., Mwimba, M., Luo, G.Z., Xu, G., Karapetyan, S., Xiang, Y., Liu, C., He, C. and Dong, X.
Pattern-triggered immunity (PTI) is the first layer of defence in plants activated upon recognizing pathogen-associated molecular patterns (PAMPs). The authors investigated how m6A modification influenced mRNA behaviour during PTI, particularly its impact on mRNA stability and translation efficiency. Using a combination of polysome profiling, mRNA stability assays, and genetic mutants, they examined how the presence or absence of m6A affects the plant’s ability to respond to pathogenic threats.
m6A was crucial for regulating the expression of defence genes, ensuring rapid and effective protein synthesis during pathogen attacks. m6A modifications contributed to fine-tuning plant immunity, providing new insights into how plants use m6A to modulate gene expression under stress. This work suggested that targeting m6A pathways could enhance disease resistance in crops.
Polysome profiling revealed that m6A-modified mRNAs related to immune responses are more associated with polysomes during PTI. m6A-modified transcripts were preferentially translated when the immune system was activated. The profile showed that mRNAs with m6A modifications shifted towards heavier polysome fractions, suggesting increased ribosome loading. This reflected that m6A enhanced translation efficiency, leading to higher protein production from these immune-related transcripts.
Certain defence-related genes were also selectively enhanced by m6A during PTI, in which the selective translation of specific transcripts was crucial for an effective immune response. The study concludes that m6A is a critical regulator of mRNA stability and translation during PTI, highlighting its role in fine-tuning plant immune responses.