November 19th
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, Salamon et al. look into neurodevelopmental regulation of translation, Ni et al. evaluate Salmonella’s ribosomal acetylation and Hedaya et al. study antisense oligonucleotides and their potential therapeutic applications.
Celf4 controls mRNA translation underlying synaptic development in the prenatal mammalian neocortex
Nature Communications, 2023
Salamon, I., Park, Y., Miškić, T., Kopić, J., Matteson, P., Page, N. F., Roque, A., McAuliffe, G. W., Favate, J., Garcia-Forn, M., Shah, P., Judaš, M., Millonig, J. H., Kostović, I., DeRubeis, S., Hart, R. P., Krsnik, Ž., & Rasin, M.-R.
In this comprehensive study of prenatal neocortical development, Salamon et al. investigated the intricacies of translational regulation, shedding light on its critical role in shaping the human fetal neocortex. Using single-nucleus RNA-seq and polysome fractionation analysis to monitor the translational status of mRNAs during different developmental phases, the authors revealed dynamic changes in the translation of transcriptionally stable mRNAs. This process is vital for orchestrating the precise spatiotemporal synthesis of proteins in the developing nervous system.
One remarkable finding was the identification of CELF4/Celf4, an RNA-binding protein (RBP) strongly associated with neurodevelopmental disorders (NDDs) and autism spectrum disorder (ASD). This RBP emerged as a key translational regulator of prenatal synaptic development, particularly in the synapse-rich subplate (SP) region of the neocortex. The study also highlighted the significance of cell-specific translational regulation, with deeper layer neurons and the SP exhibiting more pronounced translational reprogramming. Notably, CELF4 appeared to target and regulate the translation of specific presynaptic mRNAs, contributing to the formation and maintenance of prenatal neocortical synapses.
Furthermore, the research unveiled sex-specific roles of CELF4 in regulating GABAergic and glutamatergic synapses, suggesting potential links to the sex prevalence of NDDs, including ASD. This work not only provides insights into the role of translational regulation in the evolving complexity of the human fetal neocortex but also underscores the importance of understanding the contribution of sex- and cell-type-specific translational regulators in neurodevelopment. These findings hold promise for advancing our understanding of NDD pathogenesis and potential therapeutic interventions.
Global profiling of ribosomal protein acetylation reveals essentiality of acetylation homeostasis in maintaining ribosome assembly and function
Nucleic Acid Research, 2023
Ni, J., Li, S., Lai, Y., Wang, Z., Wang, D., Tan, Y., Fan, Y., Lu, J., & Yao, Y.-F.
This work by Ni et al. elucidates the pivotal role of lysine acetylation in ribosome assembly, translation efficiency, and bacterial adaptation to environmental stresses.
Salmonella, a bacterial pathogen, utilizes a complex system of ribosomal protein acetylation that involves both enzymatic (Pat) and non-enzymatic (AcP) pathways. The interplay of these pathways is essential for maintaining acetylation homeostasis, a balance that ensures proper ribosome function. Ribosomal proteins, including L24 and L7/L12, are acetylated at specific lysine residues. Acetylation of L24 is shown to impact early ribosome assembly, affecting the binding of L24 to 23S rRNA. Meanwhile, L7/L12’s acetylation status plays a crucial role in ribosome assembly and translation efficiency, influencing its interaction with elongation factors (EF-Tu) and ribosome function. The research also reveals that ribosomal protein acetylation levels vary with growth phase and environmental conditions. This dynamic acetylation process affects translation processes, making it a crucial element in bacterial adaptation to environmental stresses.
Furthermore, the study demonstrates that proper acetylation homeostasis is vital for ribosome assembly and translation efficiency, emphasizing the role of protein acetylation in regulating these essential cellular processes. Additionally, the study sheds light on how ribosome acetylation can influence bacterial susceptibility to antibiotics and the expression of genes related to environmental adaptation. In conclusion, this research uncovers the multifaceted role of ribosomal protein acetylation in Salmonella, providing insights into a novel mechanism for bacterial environmental adaptation and emphasizing the importance of maintaining acetylation homeostasis for optimal ribosome function.
Secondary structures that regulate mRNA translation provide insights for ASO-mediated modulation of cardiac hypertrophy
Nature Communications, 2023
Hedaya, O. M., Subbaiah, K. C. V., Jiang, F., Xie, L. H., Wu, J., Khor, E.-S., Zhu, M., Mathews, D. H., Proschel, C., & Yao, P.
In this article, the authors investigate the use of antisense oligonucleotides (ASOs) to modulate protein expression by targeting uORFs (upstream open reading frames) in mRNA. They explore the interaction between uORFs and double-stranded RNA (dsRNA) structures and how these interactions can be harnessed for therapeutic purposes.
The study examines the optimal distance required for dsRNA structures to cooperate with uORF start codons and influence downstream mRNA translation. Artificial reporter assays are used to illustrate the influence of dsRNA on translation initiation, suggesting that dsRNA can promote translation initiation at uORFs, potentially serving as an evolutionary mechanism for fine-tuning protein expression.
Subsequently, the authors design two classes of uORF-targeting ASOs: Class I ASOs, which form stable artificial dsRNA structures with the target mRNA, and Class II ASOs, which disrupt endogenous dsRNA structures downstream of uORFs. They demonstrate that these ASOs can either suppress or enhance the translation of the main protein-coding region, depending on their design and targeting strategy.
The study extends its findings to practical applications, such as controlling GATA4 protein expression in human cardiomyocytes and embryonic stem cell-derived cardiomyocytes. ASOs are shown to have bidirectional effects on translation, leading to cellular hypertrophy or atrophy, depending on the ASO used.
Furthermore, the research explores the therapeutic potential of uORF-targeting ASOs in animal models of cardiac hypertrophy. The administration of ASOs leads to the reduction of GATA4 protein levels, resulting in resistance to cardiac hypertrophy and improved cardiac function.
Additionally, the authors demonstrate the versatility of these ASOs by expanding their use to target the main open reading frame (mORF) of other genes, enhancing protein expression. This approach has broad implications for manipulating protein levels and holds promise for therapeutic interventions in various diseases.