March 3rd, 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, we delve into an intriguing study by Li et al. that explores the responsiveness of small peptides, encoded by lncRNA, to space conditions like radiation and microgravity. Following this, we highlight the innovative work of Foo et al., who have laid the groundwork for chromosome-level design-build-test-learn (chrDBTL) cycles. Lastly, we turn our attention to the study by Salpietro et al., which examines bi-allelic variants in GTPBP1, expanding our knowledge of genetic influences on neurodevelopmental disorders.
Large-scale ORF screening based on LC-MS to discover novel lncRNA-encoded peptides responding to ionizing radiation and microgravity
Computational and Structural Biotechnology Journal, 2023
Li, W., Yu, Y., Zhou, G., Hu, G., Li, B., Ma, H., Yan, W. and Pei, H.
This research pioneers the exploration of small peptides encoded by long non-coding RNAs (lncRNAs) within the human genome, focussing on their sensitivity to space conditions such as radiation and microgravity. Despite the knowledge that 98% of human genes transcribe into non-coding RNAs, with lncRNAs being crucial in cellular regulation, the peptides they encode, particularly those smaller than 10kD, have been largely overlooked due to technical challenges.
The primary objective of this paper was to unveil a novel dimension of the human proteome that is reactive to space environments, thereby providing insights into biological mechanisms and potential protective strategies for astronauts on space exploration missions.
In their research Li et al. successfully identified 22 novel lncRNA-encoded peptides sensitive to space conditions, using a combination of techniques like lncRNA chip sequencing and LC-MS. These peptides were analyzed for their transmembrane helix, subcellular localization, and functions, revealing a previously unknown aspect of the human proteome affected by space environments. Leveraging databases like SmProt, which catalogues small proteins identified through ribosome profiling, and the predictive GWIPS database, the research validates the expression and functionality of these peptides.
This work not only advances our understanding of lncRNA-encoded peptides in space radiation biology but also suggests their potential in protecting astronauts against space radiation and microgravity. Future efforts will delve deeper into the specific functions of these peptides, particularly their role in cell membrane and G-protein coupled receptor pathways under space conditions.
Establishing chromosomal design-build-test-learn through a synthetic chromosome and its combinatorial reconfiguration
Cell Genomics, 2023
Foo, J.L., Kitano, S., Susanto, A.V., Jin, Z., Lin, Y., Luo, Z., Huang, L., Liang, Z., Mitchell, L.A., Yang, K. and Wong, A.
In their groundbreaking research, the authors pioneered the establishment of chromosome-level design-build-test-learn cycles (chrDBTL) through the development of a synthetic Saccharomyces cerevisiae chromosome XV, named synXV. This innovative approach enabled systematic combinatorial reconfiguration of chromosomes, leveraging CRISPR-Cas9-mediated mitotic recombination with endoreduplication (CRIMiRE) for accelerated genotype-phenotype mapping and synthetic chromosome redesign. Beyond these achievements, a central focus of the study was the utilisation of synXV as a dynamic platform for translatomics, particularly through ribosome profiling.
This method allowed the researchers to conduct a detailed locus-to-locus comparison of ribosome occupancy between synXV and its wild-type counterpart, shedding light on the intricate effects of codon changes and redesigned features on translation dynamics in vivo. The findings reveal critical insights into how synthetic genomic alterations influence translation efficiency, ribosome distribution, and overall gene expression profiles. These translatomic explorations not only enhance the understanding of the fundamental principles governing translation but also underscore the potential of synthetic biology tools in elucidating complex biological processes.
The robust performance of synXV, despite extensive genomic recoding, attests to its utility as a model organism for advanced translation studies and synthetic genomics. The work establishes a precedent for the use of synthetic chromosomes in translatomic research, promising new avenues for the engineering of yeast strains with tailored phenotypes and improved understanding of translation mechanisms. Through the chrDBTL framework, synXV emerges as a versatile tool for probing biological hypotheses and advancing the field of synthetic biology.
Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome
The American Journal of Human Genetics, 2023
This study emphasises the crucial role of ribosome profiling in understanding the impact of GTP-binding proteins 1 and 2 (GTPBP1 and GTPBP2), which maintain ribosomal homeostasis, on neurodevelopmental disorders (NDDs). Previous research identified pathogenic variants in GTPBP2 as an ultra-rare cause of neurodegenerative or neurodevelopmental disorders, whereas GTPBP1’s involvement remained unexplored. The current research discovers that genetic variants in both GTPBP1 and GTPBP2 lead to a unique neurodevelopmental disorder, termed Gtpbp1/2-related ectodermal neurodevelopmental (GREND) syndrome, marked by severe neurodegeneration, epilepsy, movement disorders, ectodermal abnormalities, and distinctive craniofacial features.
The study analysed 20 individuals from 16 families displaying specific NDDs and syndromic facial features through whole-exome or whole-genome sequencing. It revealed bi-allelic variants in GTPBP1 that cause a syndrome analogous to that resulting from GTPBP2 variants, thereby broadening the spectrum of GTP-binding protein-related disorders. The functional impacts of these variants were evaluated using semi-quantitative PCR, western blot, and notably, ribosome profiling assays on fibroblasts from affected individuals.
Additionally, the study explored the effects of reducing expression of CG2017, the fruit fly ortholog of human GTPBP1/2, on Drosophila melanogaster, demonstrating motor impairments and underscoring the proteins’ vital role in central nervous system development across species. Despite identifying a loss-of-function impact of the disease-associated variants, ribosome profiling did not reveal significant abnormalities, indicating the nuanced contributions of these proteins to cellular and organismal physiology without directly altering ribosomal function.
This research expands our understanding of the bi-allelic loss-of-function variants in GTPBP1 and GTPBP2, shedding light on the complex nature of GREND syndrome. It emphasizes the need for further investigation into the underlying mechanisms of these GTP-binding proteins.