bims-micpro 2024-11-24 papers

PLoS Comput Biol. 2024 Nov;20(11): e1012543

Upstream open reading frames may contain hundreds of novel human exons.

Several recent studies have presented evidence that the human gene catalogue should be expanded to include thousands of short open reading frames (ORFs) appearing upstream or downstream of existing protein-coding genes, each of which might create an additional bicistronic transcript in humans. Here we explore an alternative hypothesis that would explain the translational and evolutionary evidence for these upstream ORFs without the need to create novel genes or bicistronic transcripts. We examined 2,199 upstream ORFs that have been proposed as high-quality candidates for novel genes, to determine if they could instead represent protein-coding exons that can be added to existing genes. We checked for the conservation of these ORFs in four recently sequenced, high-quality human genomes, and found a large majority (87.8%) to be conserved in all four as expected. We then looked for splicing evidence that would connect each upstream ORF to the downstream protein-coding gene at the same locus, thus creating a novel splicing variant using the upstream ORF as its first exon. These protein coding exon candidates were further evaluated using protein structure predictions of the protein sequences that included the proposed new exons. We determined that 541 out of 2,199 upstream ORFs have strong evidence that they can form protein coding exons that are part of an existing gene, and that the resulting protein is predicted to have similar or better structural quality than the currently annotated isoform.

DOI: https://doi.org/10.1371/journal.pcbi.1012543

Noncoding RNA Res. 2025 Feb;10 231-241

Emerging role of endogenous peptides encoded by non-coding RNAs in cancer biology.

Anna Lucia Tornesello, Andrea Cerasuolo, Noemy Starita, Sara Amiranda, Tiziana Pecchillo Cimmino, Patrizia Bonelli, Franca Maria Tuccillo, Franco Maria Buonaguro, Luigi Buonaguro, Maria Lina Tornesello.

Non-coding RNAs have long been recognized for their regulatory roles in various cellular processes, including cancer development and progression. Recent advancements have shed light on a novel aspect of non-coding RNA biology, revealing their ability to encode endogenous peptides also named micropeptides or microprotein through short open reading frames (sORFs). These small proteins play crucial roles in oncogenic processes, acting as either tumour suppressors or tumour promoters, and hold enormous potential as biomarkers for early diagnosis of cancer and as therapeutic targets. This comprehensive review highlights the state of the art on peptides encoded by long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), elucidating their regulatory functions and implications in different cancer types, including breast cancer, hepatocellular carcinoma and colorectal cancer. The review also discusses challenges and future directions in the exploration of these emerging players in cancer biology, emphasizing the importance of further investigation for their clinical translation in diagnosis and therapy.

Keywords: Biomarkers; Cancer; Micropeptide; Microprotein; Non-coding RNAs; Peptide; Therapeutic targets

DOI: https://doi.org/10.1016/j.ncrna.2024.10.006

Genome Biol Evol. 2024 Nov 21. pii: evae252. [Epub ahead of print]

TIdeS: a comprehensive framework for accurate open reading frame identification and classification in eukaryotic transcriptomes.

Xyrus X Maurer-Alcalá, Eunsoo Kim.

Studying fundamental aspects of eukaryotic biology through genetic information can face numerous challenges, including contamination and intricate biotic interactions, which are particularly pronounced when working with uncultured eukaryotes. However, existing tools for predicting open reading frames (ORFs) from transcriptomes are limited in these scenarios. Here we introduce Transcript Identification and Selection (TIdeS), a framework designed to address these non-trivial challenges associated with current 'omics approaches. Using transcriptomes from 32 taxa, representing the breadth of eukaryotic diversity, TIdeS outperforms most conventional ORF-prediction methods (i.e., TransDecoder), identifying a greater proportion of complete and in-frame ORFs. Additionally, TIdeS accurately classifies ORFs using minimal input data, even in the presence of 'heavy contamination'. This built-in flexibility extends to previously unexplored biological interactions, offering a robust single-stop solution for precise ORF predictions and subsequent decontamination. Beyond applications in phylogenomic-based studies, TIdeS provides a robust means to explore biotic interactions in eukaryotes (e.g., host-symbiont, prey-predator) and for reproducible dataset curation from transcriptomes and genomes.

Keywords: ORF prediction; biotic interactions; contamination; machine learning; phylogenomics

DOI: https://doi.org/10.1093/gbe/evae252

iScience. 2024 Nov 15. 27(11): 111212

MOTS-c modulates skeletal muscle function by directly binding and activating CK2.

MOTS-c is a mitochondrial microprotein that improves metabolism. Here, we demonstrate CK2 is a direct and functional target of MOTS-c. MOTS-c directly binds to CK2 and activates it in cell-free systems. MOTS-c administration to mice prevented skeletal muscle atrophy and enhanced muscle glucose uptake, which were blunted by suppressing CK2 activity. Interestingly, the effects of MOTS-c are tissue-specific. Systemically administered MOTS-c binds to CK2 in fat and muscle, yet stimulates CK2 activity in muscle while suppressing it in fat by differentially modifying CK2-interacting proteins. Notably, a naturally occurring MOTS-c variant, K14Q MOTS-c, has reduced binding to CK2 and does not activate it or elicit its effects. Male K14Q MOTS-c carriers exhibited a higher risk of sarcopenia and type 2 diabetes (T2D) in an age- and physical-activity-dependent manner, whereas females had an age-specific reduced risk of T2D. Altogether, these findings provide evidence that CK2 is required for MOTS-c effects.

Keywords: Physiology; cell biology

DOI: https://doi.org/10.1016/j.isci.2024.111212

Zhonghua Xin Xue Guan Bing Za Zhi. 2024 Nov 24. 52(11): 1337-1342

[Research progress on the effects of micropeptides on cardiomyocytes and their role in heart diseases].

X J Long, Q Y Zhao.

DOI: https://doi.org/10.3760/cma.j.cn112148-20240906-00516