November 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, Zhao et al. uncovered how alternative transcription start site usage (ATTSS) added a hidden layer of gene regulation in cancer. Fasken et al. identified a novel EXOSC4 gene variant (p.L187P) linked to neurodevelopmental disorders. Zhang et al. showed how CEP112 drives male fertility by orchestrating mRNA translation through liquid-liquid phase separation.
Pan-cancer transcriptome analysis reveals widespread regulation through alternative tandem transcription initiation
Science Advances, 2024
Zhao, Z., Chen, Y., Zou, X., Lin, L., Zhou, X., Cheng, X., Yang, G., Xu, Q., Gong, L., Li, L. and Ni, T.
Alternative tandem transcription start sites (ATSSs) are secondary starting points for transcription of a gene that result in mRNA variants with different 5′ untranslated regions. It has been known that tumorigenesis is promoted by abnormal transcription initiation from alternative first exon, however, the exact role and impact of alternative tandem transcription initiation in cancer were mostly unknown. The authors of this study developed a DATTSS, a novel computational tool for exploring ATSS role of gene regulation in cancer. Applying the tool to RNA-seq data from The Cancer Genome Atlas revealed extensive dysregulation of tandem TSS usage across 33 cancer types, implicating over 9,000 genes. Notably, these changes often occurred without alterations in overall gene expression levels, emphasizing the unique regulatory significance of ATTSSs.
Key findings included the correlation between TSS selection and 5′ untranslated region (UTR) modifications, which impact mRNA stability and translational efficiency. For instance, the study highlighted the 5′ UTR shortening of TIMM13 in lung adenocarcinoma, which increased protein production due to the shorter, more stable mRNA isoform. Functional experiments confirmed that this alteration enhanced cancer cell proliferation and migration, underscoring its potential role in tumor progression.
The research also linked ATTSS dynamics to epigenetic modifications, such as DNA methylation, that modulate TSS selection. Epigenetic treatments were shown to induce significant changes in ATTSS usage, revealing a complex interplay between chromatin state and transcription initiation.
In summary, this study broadens the understanding of transcriptome diversity in cancer, suggesting that ATTSS regulation contributes independently to gene expression modulation, potentially offering new prospects for therapeutic intervention and cancer biomarker development.
A biallelic variant of the RNA exosome gene, EXOSC4, associated with neurodevelopmental defects impairs RNA exosome function and translation
Journal of Biological Chemistry, 2024
Fasken, M.B., Leung, S.W., Cureton, L.A., Al-Awadi, M., Al-Kindy, A., van Hoof, A., Khoshnevis, S., Ghalei, H., Al-Maawali, A. and Corbett, A.H.
This study discusses the identification of a novel homozygous missense variant of the EXOSC4 gene (p.L187P), associated with a neurodevelopmental disorder in two siblings. This variant is linked to impairments in RNA exosome function, which plays a crucial role in RNA processing and decay. The study focuses on the transcriptomic effects caused by the defective EXOSC4 variant, exploring its impact on RNA stability and translational efficiency.
The EXOSC4 variant was discovered through exome sequencing in two affected individuals showing symptoms such as developmental delay and motor difficulties. Functional assays were conducted using both yeast and mammalian models to determine the consequences of the L187P substitution on the RNA exosome’s activity. In yeast, the variant led to decreased growth, reduced protein stability of the Rrp41 (yeast homolog of EXOSC4), and accumulation of RNA exosome substrates, indicating impaired RNA processing. This was further evidenced by disruptions in rRNA processing and decreased polysome formation, pointing to defects in ribosome biogenesis and function.
In mammalian cells, the mutated EXOSC4 showed decreased interaction with other RNA exosome subunits, further supporting the loss of functional integrity of the RNA exosome complex. These findings suggest that the L187P variant in EXOSC4 not only affects RNA stability and degradation but also impacts protein synthesis pathways crucial for cellular functioning and development.
Overall, this study advances our understanding of the molecular mechanisms by which mutations in RNA processing complexes contribute to human disease, highlighting the critical role of the RNA exosome in maintaining RNA and protein homeostasis in cells.
CEP112 coordinates translational regulation of essential fertility genes during spermiogenesis through phase separation in humans and mice
Nature Communications, 2024
Zhang, X., Huang, G., Jiang, T., Meng, L., Li, T., Zhang, G., Wu, N., Chen, X., Zhao, B., Li, N. and Wu, S.
Spermiogenesis, the process of transformation of haploid spermatids into mature sperm, requires precise control of gene expression at the post-transcriptional level.
This study investigates the role of the centrosomal protein 112 (CEP112) in the regulation of mRNA translation during spermiogenesis in both humans and mice. This protein was identified as an essential regulator that forms RNA granules through liquid-liquid phase separation (LLPS) to coordinate the translation of specific mRNAs crucial for fertility.
The study reveals that CEP112 binds and regulates key spermatogenic mRNAs, such as Fsip2, Cfap61, and Cfap74, facilitating their translation during late spermatogenesis. This is evidenced by polysome profiling and TRICK reporter assays, which show that CEP112 enhances translation efficiency by sequestering mRNAs in biomolecular condensates. Additionally, proteomic analyses of CEP112-deficient mice show downregulation of crucial sperm development proteins without corresponding mRNA level changes, indicating that CEP112 operates primarily at the translational level.
Mutations in CEP112 were identified in infertile male patients exhibiting oligoasthenoteratozoospermia, a condition that is an often cause of male infertility. Functional assays demonstrated that these mutations impaired LLPS and reduced translation efficiency of target mRNAs. The disruption of phase-separated condensates due to patient-derived CEP112 mutations directly linked the protein’s dysfunction to observed infertility phenotypes.
Overall, this study highlights the pivotal role of CEP112 in post-transcriptional control during spermiogenesis, mediated by its ability to form phase-separated condensates that regulate the translation of key fertility-related mRNAs.