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1
Markus, Damien, Aurore Pelletier, Muriel Boube, Fillip Port, Michael Boutros, François Payre, Benedikt Obermayer, and Jennifer Zanet. "The pleiotropic functions of Pri smORF peptides synchronize leg development regulators." PLOS Genetics 19, no. 10 (October 30, 2023): e1011004. http://dx.doi.org/10.1371/journal.pgen.1011004.
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The last decade witnesses the emergence of the abundant family of smORF peptides, encoded by small ORF (<100 codons), whose biological functions remain largely unexplored. Bioinformatic analyses here identify hundreds of putative smORF peptides expressed in Drosophila imaginal leg discs. Thanks to a functional screen in leg, we found smORF peptides involved in morphogenesis, including the pioneer smORF peptides Pri. Since we identified its target Ubr3 in the epidermis and pri was known to control leg development through poorly understood mechanisms, we investigated the role of Ubr3 in mediating pri function in leg. We found that pri plays several roles during leg development both in patterning and in cell survival. During larval stage, pri activates independently of Ubr3 tarsal transcriptional programs and Notch and EGFR signaling pathways, whereas at larval pupal transition, Pri peptides cooperate with Ubr3 to insure cell survival and leg morphogenesis. Our results highlight Ubr3 dependent and independent functions of Pri peptides and their pleiotropy. Moreover, we reveal that the smORF peptide family is a reservoir of overlooked developmental regulators, displaying distinct molecular functions and orchestrating leg development.
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Lyapina, Irina, Vadim Ivanov, and Igor Fesenko. "Peptidome: Chaos or Inevitability." International Journal of Molecular Sciences 22, no. 23 (December 4, 2021): 13128. http://dx.doi.org/10.3390/ijms222313128.
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Thousands of naturally occurring peptides differing in their origin, abundance and possible functions have been identified in the tissue and biological fluids of vertebrates, insects, fungi, plants and bacteria. These peptide pools are referred to as intracellular or extracellular peptidomes, and besides a small proportion of well-characterized peptide hormones and defense peptides, are poorly characterized. However, a growing body of evidence suggests that unknown bioactive peptides are hidden in the peptidomes of different organisms. In this review, we present a comprehensive overview of the mechanisms of generation and properties of peptidomes across different organisms. Based on their origin, we propose three large peptide groups—functional protein “degradome”, small open reading frame (smORF)-encoded peptides (smORFome) and specific precursor-derived peptides. The composition of peptide pools identified by mass-spectrometry analysis in human cells, plants, yeast and bacteria is compared and discussed. The functions of different peptide groups, for example the role of the “degradome” in promoting defense signaling, are also considered.
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Douka, Katerina, Isabel Birds, Dapeng Wang, Andreas Kosteletos, Sophie Clayton, Abigail Byford, Elton J. R. Vasconcelos, et al. "Cytoplasmic long noncoding RNAs are differentially regulated and translated during human neuronal differentiation." RNA 27, no. 9 (June 30, 2021): 1082–101. http://dx.doi.org/10.1261/rna.078782.121.
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The expression of long noncoding RNAs is highly enriched in the human nervous system. However, the function of neuronal lncRNAs in the cytoplasm and their potential translation remains poorly understood. Here we performed Poly-Ribo-Seq to understand the interaction of lncRNAs with the translation machinery and the functional consequences during neuronal differentiation of human SH-SY5Y cells. We discovered 237 cytoplasmic lncRNAs up-regulated during early neuronal differentiation, 58%–70% of which are associated with polysome translation complexes. Among these polysome-associated lncRNAs, we find 45 small ORFs to be actively translated, 17 specifically upon differentiation. Fifteen of 45 of the translated lncRNA-smORFs exhibit sequence conservation within Hominidea, suggesting they are under strong selective constraint in this clade. The profiling of publicly available data sets revealed that 8/45 of the translated lncRNAs are dynamically expressed during human brain development, and 22/45 are associated with cancers of the central nervous system. One translated lncRNA we discovered is LINC01116, which is induced upon differentiation and contains an 87 codon smORF exhibiting increased ribosome profiling signal upon differentiation. The resulting LINC01116 peptide localizes to neurites. Knockdown of LINC01116 results in a significant reduction of neurite length in differentiated cells, indicating it contributes to neuronal differentiation. Our findings indicate cytoplasmic lncRNAs interact with translation complexes, are a noncanonical source of novel peptides, and contribute to neuronal function and disease. Specifically, we demonstrate a novel functional role for LINC01116 during human neuronal differentiation.
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Bonilauri, Bernardo, Fabiola Barbieri Holetz, and Bruno Dallagiovanna. "Long Non-Coding RNAs Associated with Ribosomes in Human Adipose-Derived Stem Cells: From RNAs to Microproteins." Biomolecules 11, no. 11 (November 11, 2021): 1673. http://dx.doi.org/10.3390/biom11111673.
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Ribosome profiling reveals the translational dynamics of mRNAs by capturing a ribosomal footprint snapshot. Growing evidence shows that several long non-coding RNAs (lncRNAs) contain small open reading frames (smORFs) that are translated into functional peptides. The difficulty in identifying bona-fide translated smORFs is a constant challenge in experimental and bioinformatics fields due to their unconventional characteristics. This motivated us to isolate human adipose-derived stem cells (hASC) from adipose tissue and perform a ribosome profiling followed by bioinformatics analysis of transcriptome, translatome, and ribosome-protected fragments of lncRNAs. Here, we demonstrated that 222 lncRNAs were associated with the translational machinery in hASC, including the already demonstrated lncRNAs coding microproteins. The ribosomal occupancy of some transcripts was consistent with the translation of smORFs. In conclusion, we were able to identify a subset of 15 lncRNAs containing 35 smORFs that likely encode functional microproteins, including four previously demonstrated smORF-derived microproteins, suggesting a possible dual role of these lncRNAs in hASC self-renewal.
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Dozier, Christine, Audrey Montigny, Mireia Viladrich, Raphael Culerrier, Jean-Philippe Combier, Arnaud Besson, and Serge Plaza. "Small ORFs as New Regulators of Pri-miRNAs and miRNAs Expression in Human and Drosophila." International Journal of Molecular Sciences 23, no. 10 (May 20, 2022): 5764. http://dx.doi.org/10.3390/ijms23105764.
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MicroRNAs (miRNAs) are small regulatory non-coding RNAs, resulting from the cleavage of long primary transcripts (pri-miRNAs) in the nucleus by the Microprocessor complex generating precursors (pre-miRNAs) that are then exported to the cytoplasm and processed into mature miRNAs. Some miRNAs are hosted in pri-miRNAs annotated as long non-coding RNAs (lncRNAs) and defined as MIRHGs (for miRNA Host Genes). However, several lnc pri-miRNAs contain translatable small open reading frames (smORFs). If smORFs present within lncRNAs can encode functional small peptides, they can also constitute cis-regulatory elements involved in lncRNA decay. Here, we investigated the possible involvement of smORFs in the regulation of lnc pri-miRNAs in Human and Drosophila, focusing on pri-miRNAs previously shown to contain translatable smORFs. We show that smORFs regulate the expression levels of human pri-miR-155 and pri-miR-497, and Drosophila pri-miR-8 and pri-miR-14, and also affect the expression and activity of their associated miRNAs. This smORF-dependent regulation is independent of the nucleotidic and amino acidic sequences of the smORFs and is sensitive to the ribosome-stalling drug cycloheximide, suggesting the involvement of translational events. This study identifies smORFs as new cis-acting elements involved in the regulation of pri-miRNAs and miRNAs expression, in both Human and Drosophila melanogaster.
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Southan, Christopher. "Last rolls of the yoyo: Assessing the human canonical protein count." F1000Research 6 (April 7, 2017): 448. http://dx.doi.org/10.12688/f1000research.11119.1.
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In 2004, when the protein estimate from the finished human genome was only 24,000, the surprise was compounded as reviewed estimates fell to 19,000 by 2014. However, variability in the total canonical protein counts (i.e. excluding alternative splice forms) of open reading frames (ORFs) in different annotation portals persists. This work assesses these differences and possible causes. A 16-year analysis of Ensembl and UniProtKB/Swiss-Prot shows convergence to a protein number of ~20,000. The former had shown some yo-yoing, but both have now plateaued. Nine major annotation portals, reviewed at the beginning of 2017, gave a spread of counts from 21,819 down to 18,891. The 4-way cross-reference concordance (within UniProt) between Ensembl, Swiss-Prot, Entrez Gene and the Human Gene Nomenclature Committee (HGNC) drops to 18,690, indicating methodological differences in protein definitions and experimental existence support between sources. The Swiss-Prot and neXtProt evidence criteria include mass spectrometry peptide verification and also cross-references for antibody detection from the Human Protein Atlas. Notwithstanding, hundreds of Swiss-Prot entries are classified as non-coding biotypes by HGNC. The only inference that protein numbers might still rise comes from numerous reports of small ORF (smORF) discovery. However, while there have been recent cases of protein verifications from previous miss-annotation of non-coding RNA, very few have passed the Swiss-Prot curation and genome annotation thresholds. The post-genomic era has seen both advances in data generation and improvements in the human reference assembly. Notwithstanding, current numbers, while persistently discordant, show that the earlier yo-yoing has largely ceased. Given the importance to biology and biomedicine of defining the canonical human proteome, the task will need more collaborative inter-source curation combined with broader and deeper experimental confirmation in vivo and in vitro of proteins predicted in silico. The eventual closure could be well be below ~19,000.
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Wan, Linrong, Wenfu Xiao, Ziyan Huang, Anlian Zhou, Yaming Jiang, Bangxing Zou, Binbin Liu, Cao Deng, and Youhong Zhang. "Systematic identification of smORFs in domestic silkworm (Bombyx mori)." PeerJ 11 (January 13, 2023): e14682. http://dx.doi.org/10.7717/peerj.14682.
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The silkworm (Bombyx mori) is not only an excellent model species, but also an important agricultural economic insect. Taking it as the research object, its advantages of low maintenance cost and no biohazard risks are considered. Small open reading frames (smORFs) are an important class of genomic elements that can produce bioactive peptides. However, the smORFs in silkworm had been poorly identified and studied. To further study the smORFs in silkworm, systematic genome-wide identification is essential. Here, we identified and analyzed smORFs in the silkworm using comprehensive methods. Our results showed that at least 738 highly reliable smORFs were found in B. mori and that 34,401 possible smORFs were partially supported. We also identified some differentially expressed and tissue-specific-expressed smORFs, which may be closely related to the characteristics and functions of the tissues. This article provides a basis for subsequent research on smORFs in silkworm, and also hopes to provide a reference point for future research methods for smORFs in other species.
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Cao, Yipeng, Rui Yang, Imshik Lee, Wenwen Zhang, Jiana Sun, Xiangfei Meng, and Wei Wang. "Prediction of LncRNA-encoded small peptides in glioma and oligomer channel functional analysis using in silico approaches." PLOS ONE 16, no. 3 (March 18, 2021): e0248634. http://dx.doi.org/10.1371/journal.pone.0248634.
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Glioma is a lethal malignant brain cancer, and many reports have shown that abnormalities in the behavior of water and ion channels play an important role in regulating tumor proliferation, migration, apoptosis, and differentiation. Recently, new studies have suggested that some long noncoding RNAs containing small open reading frames can encode small peptides and form oligomers for water or ion regulation. However, because the peptides are difficult to identify, their functional mechanisms are far from being clearly understood. In this study, we used bioinformatics methods to identify and evaluate lncRNAs, which may encode small transmembrane peptides in gliomas. Combining ab initio homology modeling, molecular dynamics simulations, and free energy calculations, we constructed a predictive model and predicted the oligomer channel activity of peptides by identifying the lncRNA ORFs. We found that one key hub lncRNA, namely, DLEU1, which contains two smORFs (ORF1 and ORF8), encodes small peptides that form pentameric channels. The mechanics of water and ion (Na+ and Cl-) transport through this pentameric channel were simulated. The potential mean force of the H2O molecules along the two ORF-encoded peptide channels indicated that the energy barrier was different between ORF1 and ORF8. The ORF1-encoded peptide pentamer acted as a self-assembled water channel but not as an ion channel, and the ORF8 permeated neither ions nor water. This work provides new methods and theoretical support for further elucidation of the function of lncRNA-encoded small peptides and their role in cancer. Additionally, this study provides a theoretical basis for drug development.
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Magny, Emile G., Jose Ignacio Pueyo, Frances M. G. Pearl, Miguel Angel Cespedes, Jeremy E. Niven, Sarah A. Bishop, and Juan Pablo Couso. "Conserved Regulation of Cardiac Calcium Uptake by Peptides Encoded in Small Open Reading Frames." Science 341, no. 6150 (August 22, 2013): 1116–20. http://dx.doi.org/10.1126/science.1238802.
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Small open reading frames (smORFs) are short DNA sequences that are able to encode small peptides of less than 100 amino acids. Study of these elements has been neglected despite thousands existing in our genomes. We and others previously showed that peptides as short as 11 amino acids are translated and provide essential functions during insect development. Here, we describe two peptides of less than 30 amino acids regulating calcium transport, and hence influencing regular muscle contraction, in the Drosophila heart. These peptides seem conserved for more than 550 million years in a range of species from flies to humans, in which they have been implicated in cardiac pathologies. Such conservation suggests that the mechanisms for heart regulation are ancient and that smORFs may be a fundamental genome component that should be studied systematically.
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Dragomir, Mihnea P., Ganiraju C. Manyam, Leonie Florence Ott, Léa Berland, Erik Knutsen, Cristina Ivan, Leonard Lipovich, Bradley M. Broom, and George A. Calin. "FuncPEP: A Database of Functional Peptides Encoded by Non-Coding RNAs." Non-Coding RNA 6, no. 4 (September 23, 2020): 41. http://dx.doi.org/10.3390/ncrna6040041.
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Non-coding RNAs (ncRNAs) are essential players in many cellular processes, from normal development to oncogenic transformation. Initially, ncRNAs were defined as transcripts that lacked an open reading frame (ORF). However, multiple lines of evidence suggest that certain ncRNAs encode small peptides of less than 100 amino acids. The sequences encoding these peptides are known as small open reading frames (smORFs), many initiating with the traditional AUG start codon but terminating with atypical stop codons, suggesting a different biogenesis. The ncRNA-encoded peptides (ncPEPs) are gradually becoming appreciated as a new class of functional molecules that contribute to diverse cellular processes, and are deregulated in different diseases contributing to pathogenesis. As multiple publications have identified unique ncPEPs, we appreciated the need for assembling a new web resource that could gather information about these functional ncPEPs. We developed FuncPEP, a new database of functional ncRNA encoded peptides, containing all experimentally validated and functionally characterized ncPEPs. Currently, FuncPEP includes a comprehensive annotation of 112 functional ncPEPs and specific details regarding the ncRNA transcripts that encode these peptides. We believe that FuncPEP will serve as a platform for further deciphering the biologic significance and medical use of ncPEPs. The link for FuncPEP database can be found at the end of the Introduction Section.
11
Immarigeon, Clément, Yohan Frei, Sofie Y. N. Delbare, Dragan Gligorov, Pedro Machado Almeida, Jasmine Grey, Léa Fabbro, et al. "Identification of a micropeptide and multiple secondary cell genes that modulateDrosophilamale reproductive success." Proceedings of the National Academy of Sciences 118, no. 15 (April 5, 2021): e2001897118. http://dx.doi.org/10.1073/pnas.2001897118.
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Even in well-characterized genomes, many transcripts are considered noncoding RNAs (ncRNAs) simply due to the absence of large open reading frames (ORFs). However, it is now becoming clear that many small ORFs (smORFs) produce peptides with important biological functions. In the process of characterizing the ribosome-bound transcriptome of an important cell type of the seminal fluid-producing accessory gland ofDrosophila melanogaster, we detected an RNA, previously thought to be noncoding, calledmale-specific abdominal(msa). Notably,msais nested in the HOX gene cluster of the Bithorax complex and is known to contain a micro-RNA within one of its introns. We find that this RNA encodes a “micropeptide” (9 or 20 amino acids, MSAmiP) that is expressed exclusively in the secondary cells of the male accessory gland, where it seems to accumulate in nuclei. Importantly, loss of function of this micropeptide causes defects in sperm competition. In addition to bringing insights into the biology of a rare cell type, this work underlines the importance of small peptides, a class of molecules that is now emerging as important actors in complex biological processes.
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Pueyo, Jose I., Jorge Salazar, Carolina Grincho, Jimena Berni, Benjamin P. Towler, and Sarah F. Newbury. "Purriato is a conserved small open reading frame gene that interacts with the CASA pathway to regulate muscle homeostasis and epithelial tissue growth in Drosophila." Frontiers in Cell and Developmental Biology 11 (March 10, 2023). http://dx.doi.org/10.3389/fcell.2023.1117454.
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Recent advances in proteogenomic techniques and bioinformatic pipelines have permitted the detection of thousands of translated small Open Reading Frames (smORFs), which contain less than 100 codons, in eukaryotic genomes. Hundreds of these actively translated smORFs display conserved sequence, structure and evolutionary signatures indicating that the translated peptides could fulfil important biological roles. Despite their abundance, only tens of smORF genes have been fully characterised; these act mainly as regulators of canonical proteins involved in essential cellular processes. Importantly, some of these smORFs display conserved functions with their mutations being associated with pathogenesis. Thus, investigating smORF roles in Drosophila will not only expand our understanding of their functions but it may have an impact in human health. Here we describe the function of a novel and essential Drosophila smORF gene named purriato (prto). prto belongs to an ancient gene family whose members have expanded throughout the Protostomia clade. prto encodes a transmembrane peptide which is localized in endo-lysosomes and perinuclear and plasma membranes. prto is dynamically expressed in mesodermal tissues and imaginal discs. Targeted prto knockdown (KD) in these organs results in changes in nuclear morphology and endo-lysosomal distributions correlating with the loss of sarcomeric homeostasis in muscles and reduction of mitosis in wing discs. Consequently, prto KD mutants display severe reduction of motility, and shorter wings. Finally, our genetic interaction experiments show that prto function is closely associated to the CASA pathway, a conserved mechanism involved in turnover of mis-folded proteins and linked to muscle dystrophies and neurodegenerative diseases. Thus, this study shows the relevance of smORFs in regulating important cellular functions and supports the systematic characterisation of this class of genes to understand their functions and evolution.
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Bosch, Justin A., Berrak Ugur, Israel Pichardo-Casas, Jordan Rabasco, Felipe Escobedo, Zhongyuan Zuo, Ben Brown, et al. "Two neuronal peptides encoded from a single transcript regulate mitochondrial complex III in Drosophila." eLife 11 (November 8, 2022). http://dx.doi.org/10.7554/elife.82709.
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Naturally produced peptides (<100 amino acids) are important regulators of physiology, development, and metabolism. Recent studies have predicted that thousands of peptides may be translated from transcripts containing small open reading frames (smORFs). Here, we describe two peptides in Drosophila encoded by conserved smORFs, Sloth1 and Sloth2. These peptides are translated from the same bicistronic transcript and share sequence similarities, suggesting that they encode paralogs. Yet, Sloth1 and Sloth2 are not functionally redundant, and loss of either peptide causes animal lethality, reduced neuronal function, impaired mitochondrial function, and neurodegeneration. We provide evidence that Sloth1/2 are highly expressed in neurons, imported to mitochondria, and regulate mitochondrial complex III assembly. These results suggest that phenotypic analysis of smORF genes in Drosophila can provide a wealth of information on the biological functions of this poorly characterized class of genes.
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Aspden, Julie L., Ying Chen Eyre-Walker, Rose J. Phillips, Unum Amin, Muhammad Ali S. Mumtaz, Michele Brocard, and Juan-Pablo Couso. "Extensive translation of small Open Reading Frames revealed by Poly-Ribo-Seq." eLife 3 (August 21, 2014). http://dx.doi.org/10.7554/elife.03528.
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Thousands of small Open Reading Frames (smORFs) with the potential to encode small peptides of fewer than 100 amino acids exist in our genomes. However, the number of smORFs actually translated, and their molecular and functional roles are still unclear. In this study, we present a genome-wide assessment of smORF translation by ribosomal profiling of polysomal fractions in Drosophila. We detect two types of smORFs bound by multiple ribosomes and thus undergoing productive translation. The ‘longer’ smORFs of around 80 amino acids resemble canonical proteins in translational metrics and conservation, and display a propensity to contain transmembrane motifs. The ‘dwarf’ smORFs are in general shorter (around 20 amino-acid long), are mostly found in 5′-UTRs and non-coding RNAs, are less well conserved, and have no bioinformatic indicators of peptide function. Our findings indicate that thousands of smORFs are translated in metazoan genomes, reinforcing the idea that smORFs are an abundant and fundamental genome component.
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Ventroux, Magali, and Marie-Francoise Noirot-Gros. "Prophage-encoded small protein YqaH counteracts the activities of the replication initiator DnaA in Bacillus subtilis." Microbiology 168, no. 11 (November 29, 2022). http://dx.doi.org/10.1099/mic.0.001268.
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Bacterial genomes harbour cryptic prophages that are mostly transcriptionally silent with many unannotated genes. Still, cryptic prophages may contribute to their host fitness and phenotypes. In Bacillus subtilis, the yqaF-yqaN operon belongs to the prophage element skin, and is tightly repressed by the Xre-like repressor SknR. This operon contains several small ORFs (smORFs) potentially encoding small-sized proteins. The smORF-encoded peptide YqaH was previously reported to bind to the replication initiator DnaA. Here, using a yeast two-hybrid assay, we found that YqaH binds to the DNA binding domain IV of DnaA and interacts with Spo0A, a master regulator of sporulation. We isolated single amino acid substitutions in YqaH that abolished the interaction with DnaA but not with Spo0A. Then, using a plasmid-based inducible system to overexpress yqaH WT and mutant derivatives, we studied in B. subtilis the phenotypes associated with the specific loss-of-interaction with DnaA (DnaA_LOI). We found that expression of yqaH carrying DnaA_LOI mutations abolished the deleterious effects of yqaH WT expression on chromosome segregation, replication initiation and DnaA-regulated transcription. When YqaH was induced after vegetative growth, DnaA_LOI mutations abolished the drastic effects of YqaH WT on sporulation and biofilm formation. Thus, YqaH inhibits replication, sporulation and biofilm formation mainly by antagonizing DnaA in a manner that is independent of the cell cycle checkpoint Sda.
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Peng, Zhao, Jiaqiang Li, Xingpeng Jiang, and Cuihong Wan. "sOCP: a framework predicting smORF coding potential based on TIS and in-frame features and effectively applied in the human genome." Briefings in Bioinformatics 25, no. 3 (March 27, 2024). http://dx.doi.org/10.1093/bib/bbae147.
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Abstract Small open reading frames (smORFs) have been acknowledged to play various roles on essential biological pathways and affect human beings from diabetes to tumorigenesis. Predicting smORFs in silico is quite a prerequisite for processing the omics data. Here, we proposed the smORF-coding-potential-predicting framework, sOCP, which provides functions to construct a model for predicting novel smORFs in some species. The sOCP model constructed in human was based on in-frame features and the nucleotide bias around the start codon, and the small feature subset was proved to be competent enough and avoid overfitting problems for complicated models. It showed more advanced prediction metrics than previous methods and could correlate closely with experimental evidence in a heterogeneous dataset. The model was applied to Rattus norvegicus and exhibited satisfactory performance. We then scanned smORFs with ATG and non-ATG start codons from the human genome and generated a database containing about a million novel smORFs with coding potential. Around 72 000 smORFs are located on the lncRNA regions of the genome. The smORF-encoded peptides may be involved in biological pathways rare for canonical proteins, including glucocorticoid catabolic process and the prokaryotic defense system. Our work provides a model and database for human smORF investigation and a convenient tool for further smORF prediction in other species.
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Fan, Si-Min, Ze-Qi Li, Shi-Zhe Zhang, Liang-Yu Chen, Xi-Ying Wei, Jian Liang, Xin-Qing Zhao, and Chun Su. "Multi-integrated approach for unraveling small open reading frames potentially associated with secondary metabolism in Streptomyces." mSystems, September 15, 2023. http://dx.doi.org/10.1128/msystems.00245-23.
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ABSTRACT Small open reading frames (smORFs) are widely distributed in various living organisms. However, their functions remain largely unexplored. In addition, annotation and detection of smORFs are limited using existing methods and hindered by their specific properties. In this study, we systematically investigated smORFs and smORF-encoded peptides (SEPs) in Streptomyces , which are well-known bacterial producers of diverse bioactive secondary metabolites. We established a peptidogenomic workflow based on multi-integrated comprehensive database search and database-independent de novo sequencing to identify smORFs in Streptomyces xinghaiensis NRRL B-24674 T (S187). In addition, we described SEPome related to the secondary metabolism, which include 68 novel SEPs and 79 common smORFs with Streptomyces coelicolor A3 (2). Functional analysis of universal smORFs revealed enrichment in biosynthetic processes, stress response, ribosomes, and nucleic acid binding. Meanwhile, 5 Cryptic smORF-encoded Peptides (CSEPs) distributed in non-annotated regions of the genome, and non-coding RNAs could encode for CSEPs. A total of 66 new RNAs, including 32 non-coding RNAs (ncRNAs) were revealed, and 4 ncRNA-encoded peptides were identified. Furthermore, an investigation of carbon metabolism showed that NagE functions in spore formation and secondary metabolism in Streptomyces . Particularly, NagE was observed to function in the biosynthesis of anti-complement agents in S. xinghaiensis, suggesting a novel role of the phosphoenolpyruvate phosphotransferase system in microbial secondary metabolism. We thus provide an effective strategy for analyzing public data sets of model strains to identify smORFs for non-model species. The ncRNAs and SEPs present rich sources for engineering streptomycetes to produce bioactive compounds. IMPORTANCE Due to their small size and special chemical features, small open reading frame (smORF)-encoding peptides (SEPs) are often neglected. However, they may play critical roles in regulating gene expression, enzyme activity, and metabolite production. Studies on bacterial microproteins have mainly focused on pathogenic bacteria, which are importance to systematically investigate SEPs in streptomycetes and are rich sources of bioactive secondary metabolites. Our study is the first to perform a global identification of smORFs in streptomycetes. We established a peptidogenomic workflow for non-model microbial strains and identified multiple novel smORFs that are potentially linked to secondary metabolism in streptomycetes. Our multi-integrated approach in this study is meaningful to improve the quality and quantity of the detected smORFs. Ultimately, the workflow we established could be extended to other organisms and would benefit the genome mining of microproteins with critical functions for regulation and engineering useful microorganisms.
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Guerra-Almeida, Diego, Diogo Antonio Tschoeke, and Rodrigo Nunes-da-Fonseca. "Understanding small ORF diversity through a comprehensive transcription feature classification." DNA Research 28, no. 5 (July 7, 2021). http://dx.doi.org/10.1093/dnares/dsab007.
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Abstract Small open reading frames (small ORFs/sORFs/smORFs) are potentially coding sequences smaller than 100 codons that have historically been considered junk DNA by gene prediction software and in annotation screening; however, the advent of next-generation sequencing has contributed to the deeper investigation of junk DNA regions and their transcription products, resulting in the emergence of smORFs as a new focus of interest in systems biology. Several smORF peptides were recently reported in non-canonical mRNAs as new players in numerous biological contexts; however, their relevance is still overlooked in coding potential analysis. Hence, this review proposes a smORF classification based on transcriptional features, discussing the most promising approaches to investigate smORFs based on their different characteristics. First, smORFs were divided into non-expressed (intergenic) and expressed (genic) smORFs. Second, genic smORFs were classified as smORFs located in non-coding RNAs (ncRNAs) or canonical mRNAs. Finally, smORFs in ncRNAs were further subdivided into sequences located in small or long RNAs, whereas smORFs located in canonical mRNAs were subdivided into several specific classes depending on their localization along the gene. We hope that this review provides new insights into large-scale annotations and reinforces the role of smORFs as essential components of a hidden coding DNA world.
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Jain, Niyati, Felix Richter, Ivan Adzhubei, Andrew J. Sharp, and Bruce D. Gelb. "Small open reading frames: a comparative genetics approach to validation." BMC Genomics 24, no. 1 (May 1, 2023). http://dx.doi.org/10.1186/s12864-023-09311-7.
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AbstractOpen reading frames (ORFs) with fewer than 100 codons are generally not annotated in genomes, although bona fide genes of that size are known. Newer biochemical studies have suggested that thousands of small protein-coding ORFs (smORFs) may exist in the human genome, but the true number and the biological significance of the micropeptides they encode remain uncertain. Here, we used a comparative genomics approach to identify high-confidence smORFs that are likely protein-coding. We identified 3,326 high-confidence smORFs using constraint within human populations and evolutionary conservation as additional lines of evidence. Next, we validated that, as a group, our high-confidence smORFs are conserved at the amino-acid level rather than merely residing in highly conserved non-coding regions. Finally, we found that high-confidence smORFs are enriched among disease-associated variants from GWAS. Overall, our results highlight that smORF-encoded peptides likely have important functional roles in human disease.
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Fesenko, Igor, Svetlana A. Shabalina, Anna Mamaeva, Andrey Knyazev, Anna Glushkevich, Irina Lyapina, Rustam Ziganshin, et al. "A vast pool of lineage-specific microproteins encoded by long non-coding RNAs in plants." Nucleic Acids Research, September 27, 2021. http://dx.doi.org/10.1093/nar/gkab816.
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Abstract Pervasive transcription of eukaryotic genomes results in expression of long non-coding RNAs (lncRNAs) most of which are poorly conserved in evolution and appear to be non-functional. However, some lncRNAs have been shown to perform specific functions, in particular, transcription regulation. Thousands of small open reading frames (smORFs, <100 codons) located on lncRNAs potentially might be translated into peptides or microproteins. We report a comprehensive analysis of the conservation and evolutionary trajectories of lncRNAs-smORFs from the moss Physcomitrium patens across transcriptomes of 479 plant species. Although thousands of smORFs are subject to substantial purifying selection, the majority of the smORFs appear to be evolutionary young and could represent a major pool for functional innovation. Using nanopore RNA sequencing, we show that, on average, the transcriptional level of conserved smORFs is higher than that of non-conserved smORFs. Proteomic analysis confirmed translation of 82 novel species-specific smORFs. Numerous conserved smORFs containing low complexity regions (LCRs) or transmembrane domains were identified, the biological functions of a selected LCR-smORF were demonstrated experimentally. Thus, microproteins encoded by smORFs are a major, functionally diverse component of the plant proteome.
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Sruthi, K. Bharathan, Athira Menon, Akash P, and Eppurath Vasudevan Soniya. "Pervasive translation of small open reading frames in plant long non-coding RNAs." Frontiers in Plant Science 13 (October 24, 2022). http://dx.doi.org/10.3389/fpls.2022.975938.
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Long non-coding RNAs (lncRNAs) are primarily recognized as non-coding transcripts longer than 200 nucleotides with low coding potential and are present in both eukaryotes and prokaryotes. Recent findings reveal that lncRNAs can code for micropeptides in various species. Micropeptides are generated from small open reading frames (smORFs) and have been discovered frequently in short mRNAs and non-coding RNAs, such as lncRNAs, circular RNAs, and pri-miRNAs. The most accepted definition of a smORF is an ORF containing fewer than 100 codons, and ribosome profiling and mass spectrometry are the most prevalent experimental techniques used to identify them. Although the majority of micropeptides perform critical roles throughout plant developmental processes and stress conditions, only a handful of their functions have been verified to date. Even though more research is being directed toward identifying micropeptides, there is still a dearth of information regarding these peptides in plants. This review outlines the lncRNA-encoded peptides, the evolutionary roles of such peptides in plants, and the techniques used to identify them. It also describes the functions of the pri-miRNA and circRNA-encoded peptides that have been identified in plants.
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Hara, Tomoaki, Sikun Meng, Yoshiko Tsuji, Yasuko Arao, Yoshiko Saito, Hiromichi Sato, Daisuke Motooka, Shizuka Uchida, and Hideshi Ishii. "RN7SL1 may be translated under oncogenic conditions." Proceedings of the National Academy of Sciences 121, no. 12 (March 13, 2024). http://dx.doi.org/10.1073/pnas.2312322121.
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RN7SL1 (RNA component of signal recognition particle 7SL1), a component of the signal recognition particle, is a non-coding RNA possessing a small ORF (smORF). However, whether it is translated into peptides is unknown. Here, we generated the RN7SL1-Green Fluorescent Protein (GFP) gene, in which the smORF of RN7SL1 was replaced by GFP, introduced it into 293T cells, and observed cells emitting GFP fluorescence. Furthermore, RNA-seq of GFP-positive cells revealed that they were in an oncogenic state, suggesting that RN7SL1 smORF may be translated under special conditions.
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Dib, Azza, Jennifer Zanet, Alexandra Mancheno-Ferris, Maylis Gallois, Damien Markus, Philippe Valenti, Simon Marques-Prieto, et al. "Pri smORF Peptides Are Wide Mediators of Ecdysone Signaling, Contributing to Shape Spatiotemporal Responses." Frontiers in Genetics 12 (August 30, 2021). http://dx.doi.org/10.3389/fgene.2021.714152.
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There is growing evidence that peptides encoded by small open-reading frames (sORF or smORF) can fulfill various cellular functions and define a novel class regulatory molecules. To which extend transcripts encoding only smORF peptides compare with canonical protein-coding genes, yet remain poorly understood. In particular, little is known on whether and how smORF-encoding RNAs might need tightly regulated expression within a given tissue, at a given time during development. We addressed these questions through the analysis of Drosophila polished rice (pri, a.k.a. tarsal less or mille pattes), which encodes four smORF peptides (11–32 amino acids in length) required at several stages of development. Previous work has shown that the expression of pri during epidermal development is regulated in the response to ecdysone, the major steroid hormone in insects. Here, we show that pri transcription is strongly upregulated by ecdysone across a large panel of cell types, suggesting that pri is a core component of ecdysone response. Although pri is produced as an intron-less short transcript (1.5 kb), genetic assays reveal that the developmental functions of pri require an unexpectedly large array of enhancers (spanning over 50 kb), driving a variety of spatiotemporal patterns of pri expression across developing tissues. Furthermore, we found that separate pri enhancers are directly activated by the ecdysone nuclear receptor (EcR) and display distinct regulatory modes between developmental tissues and/or stages. Alike major developmental genes, the expression of pri in a given tissue often involves several enhancers driving apparently redundant (or shadow) expression, while individual pri enhancers can harbor pleiotropic functions across tissues. Taken together, these data reveal the broad role of Pri smORF peptides in ecdysone signaling and show that the cis-regulatory architecture of the pri gene contributes to shape distinct spatial and temporal patterns of ecdysone response throughout development.
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Hu, Fengyuan, Jia Lu, Louise S. Matheson, Manuel D. Díaz-Muñoz, Alexander Saveliev, and Martin Turner. "ORFLine: a bioinformatic pipeline to prioritize small open reading frames identifies candidate secreted small proteins from lymphocytes." Bioinformatics, May 10, 2021. http://dx.doi.org/10.1093/bioinformatics/btab339.
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Abstract Motivation The annotation of small open reading frames (smORFs) of <100 codons (<300 nucleotides) is challenging due to the large number of such sequences in the genome. Results In this study, we developed a computational pipeline, which we have named ORFLine, that stringently identifies smORFs and classifies them according to their position within transcripts. We identified a total of 5744 unique smORFs in datasets from mouse B and T lymphocytes and systematically characterized them using ORFLine. We further searched smORFs for the presence of a signal peptide, which predicted known secreted chemokines as well as novel micropeptides. Four novel micropeptides show evidence of secretion and are therefore candidate mediators of immunoregulatory functions. Availability and implementation Freely available on the web at https://github.com/boboppie/ORFLine. Supplementary information Supplementary data are available at Bioinformatics online.
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Magny, Emile G., Ana Isabel Platero, Sarah A. Bishop, Jose I. Pueyo, Daniel Aguilar-Hidalgo, and Juan Pablo Couso. "Pegasus, a small extracellular peptide enhancing short-range diffusion of Wingless." Nature Communications 12, no. 1 (September 27, 2021). http://dx.doi.org/10.1038/s41467-021-25785-z.
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AbstractSmall Open Reading Frames (smORFs) coding for peptides of less than 100 amino-acids are an enigmatic and pervasive gene class, found in the tens of thousands in metazoan genomes. Here we reveal a short 80 amino-acid peptide (Pegasus) which enhances Wingless/Wnt1 protein short-range diffusion and signalling. During Drosophila wing development, Wingless has sequential functions, including late induction of proneural gene expression and wing margin development. Pegasus mutants produce wing margin defects and proneural expression loss similar to those of Wingless. Pegasus is secreted, and co-localizes and co-immunoprecipitates with Wingless, suggesting their physical interaction. Finally, measurements of fixed and in-vivo Wingless gradients support that Pegasus increases Wingless diffusion in order to enhance its signalling. Our results unveil a new element in Wingless signalling and clarify the patterning role of Wingless diffusion, while corroborating the link between small open reading frame peptides, and regulation of known proteins with membrane-related functions.
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Coelho, Luis Pedro, Célio Dias Santos‐Júnior, and Cesar de la Fuente‐Nunez. "Challenges in computational discovery of bioactive peptides in ’omics data." PROTEOMICS, March 8, 2024. http://dx.doi.org/10.1002/pmic.202300105.
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AbstractPeptides have a plethora of activities in biological systems that can potentially be exploited biotechnologically. Several peptides are used clinically, as well as in industry and agriculture. The increase in available ’omics data has recently provided a large opportunity for mining novel enzymes, biosynthetic gene clusters, and molecules. While these data primarily consist of DNA sequences, other types of data provide important complementary information. Due to their size, the approaches proven successful at discovering novel proteins of canonical size cannot be naïvely applied to the discovery of peptides. Peptides can be encoded directly in the genome as short open reading frames (smORFs), or they can be derived from larger proteins by proteolysis. Both of these peptide classes pose challenges as simple methods for their prediction result in large numbers of false positives. Similarly, functional annotation of larger proteins, traditionally based on sequence similarity to infer orthology and then transferring functions between characterized proteins and uncharacterized ones, cannot be applied for short sequences. The use of these techniques is much more limited and alternative approaches based on machine learning are used instead. Here, we review the limitations of traditional methods as well as the alternative methods that have recently been developed for discovering novel bioactive peptides with a focus on prokaryotic genomes and metagenomes.
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Gallois, Maylis, Delphine Menoret, Simon Marques-Prieto, Audrey Montigny, Philippe Valenti, Bernard Moussian, Serge Plaza, François Payre, and Hélène Chanut-Delalande. "Pri peptides temporally coordinate transcriptional programs during epidermal differentiation." Science Advances 10, no. 6 (February 9, 2024). http://dx.doi.org/10.1126/sciadv.adg8816.
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To achieve a highly differentiated state, cells undergo multiple transcriptional processes whose coordination and timing are not well understood. In Drosophila embryonic epidermal cells, polished-rice (Pri) smORF peptides act as temporal mediators of ecdysone to activate a transcriptional program leading to cell shape remodeling. Here, we show that the ecdysone/Pri axis concomitantly represses the transcription of a large subset of cuticle genes to ensure proper differentiation of the insect exoskeleton. The repression relies on the transcription factor Ken and persists for several days throughout early larval stages, during which a soft cuticle allows larval crawling. The onset of these cuticle genes normally awaits the end of larval stages when the rigid pupal case assembles, and their premature expression triggers abnormal sclerotization of the larval cuticle. These results uncovered a temporal switch to set up distinct structures of cuticles adapted to the animal lifestyle and which might be involved in the evolutionary history of insects.
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Li, Hui, Li Xiao, Lili Zhang, Jiarui Wu, Bin Wei, Ninghui Sun, and Yi Zhao. "FSPP: A Tool for Genome-Wide Prediction of smORF-Encoded Peptides and Their Functions." Frontiers in Genetics 9 (April 5, 2018). http://dx.doi.org/10.3389/fgene.2018.00096.
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Moysidis, Dimitrios V., Stylianos Daios, Vasileios Anastasiou, Alexandros C. Liatsos, Andreas S. Papazoglou, Efstratios Karagiannidis, Vasileios Kamperidis, et al. "Association of clinical, laboratory and imaging biomarkers with the occurrence of acute myocardial infarction in patients without standard modifiable risk factors – rationale and design of the “Beyond-SMuRFs Study”." BMC Cardiovascular Disorders 23, no. 1 (March 23, 2023). http://dx.doi.org/10.1186/s12872-023-03180-4.
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Abstract Background Acute myocardial infarction (AMI) remains the leading cause of mortality worldwide. The majority of patients who suffer an AMI have a history of at least one of the standard modifiable risk factors (SMuRFs): smoking, hypertension, dyslipidemia, and diabetes mellitus. However, emerging scientific evidence recognizes a clinically significant and increasing proportion of patients presenting with AMI without any SMuRF (SMuRF-less patients). To date, there are no adequate data to define specific risk factors or biomarkers associated with the development of AMIs in these patients. Methods The ‘‘Beyond-SMuRFs Study’’ is a prospective, non-interventional cohort trial designed to enroll patients with AMI and no previous coronary intervention history, who undergo coronary angiography in two academic hospitals in Thessaloniki, Greece. The rationale of the study is to investigate potential relations between SMuRF-less AMIs and the clinical, laboratory and imaging profile of patients, by comparing parameters between patients with and without SMuRFs. Complete demographic and comprehensive clinical data will be recorded, Venous blood samples will be collected before coronary angiography and the following parameters will be measured: total blood count, standard biochemistry parameters, coagulation tests, hormone levels, glycosylated hemoglobin, N- terminal pro-B-type natriuretic peptide and high-sensitivity troponin T levels- as well as serum levels of novel atherosclerosis indicators and pro-inflammatory biomarkers. Furthermore, all participants will undergo a complete and comprehensive transthoracic echocardiographic assessment according to a pre-specified protocol within 24 h from admission. Among others, 2D-speckle-tracking echocardiographic analysis of cardiac chambers and non-invasive calculation of myocardial work indices for the left ventricle will be performed. Moreover, all patients will be assessed for angiographic parameters and the complexity of coronary artery disease using the SYNTAX score. Multivariable linear and logistic regression models will be used to phenotypically characterize SMuRF-less patients and investigate independent clinical, laboratory, echocardiographic and angiographic biomarkers-predictors of SMuRF-less status in AMI.The first patient was enrolled in March 2022 and completion of enrollment is expected until December 2023. Discussion The ‘‘Beyond-SmuRFs’’ study is an ongoing prospective trial aiming to investigate potential clinical, laboratory and imaging biomarkers associated with the occurrence of AMIs in SMuRF-less patients. The configuration of these patients’ profiles could lead to the development of personalized risk-stratification models predicting the occurrence of cardiovascular events in SΜuRF-less individuals. Trial Registration ClinicalTrials.gov Identifier: NCT05535582 / September 10, 2022.
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Ray, Suparna, Miriam I. Rosenberg, Hélène Chanut-Delalande, Amélie Decaras, Barbara Schwertner, William Toubiana, Tzach Auman, et al. "The mlpt/Ubr3/Svb module comprises an ancient developmental switch for embryonic patterning." eLife 8 (March 21, 2019). http://dx.doi.org/10.7554/elife.39748.
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Small open reading frames (smORFs) encoding ‘micropeptides’ exhibit remarkable evolutionary complexity. Conserved peptides encoded by mille-pattes (mlpt)/polished rice (pri)/tarsal less (tal) are essential for embryo segmentation in Tribolium but, in Drosophila, function in terminal epidermal differentiation and patterning of adult legs. Here, we show that a molecular complex identified in Drosophila epidermal differentiation, comprising Mlpt peptides, ubiquitin-ligase Ubr3 and transcription factor Shavenbaby (Svb), represents an ancient developmental module required for early insect embryo patterning. We find that loss of segmentation function for this module in flies evolved concomitantly with restriction of Svb expression in early Drosophila embryos. Consistent with this observation, artificially restoring early Svb expression in flies causes segmentation defects that depend on mlpt function, demonstrating enduring potency of an ancestral developmental switch despite evolving embryonic patterning modes. These results highlight the evolutionary plasticity of conserved molecular complexes under the constraints of essential genetic networks.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).
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Turchetti, Benedetta, Pietro Buzzini, and Marcelo Baeza. "A genomic approach to analyze the cold adaptation of yeasts isolated from Italian Alps." Frontiers in Microbiology 13 (November 8, 2022). http://dx.doi.org/10.3389/fmicb.2022.1026102.
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Microorganisms including yeasts are responsible for mineralization of organic matter in cold regions, and their characterization is critical to elucidate the ecology of such environments on Earth. Strategies developed by yeasts to survive in cold environments have been increasingly studied in the last years and applied to different biotechnological applications, but their knowledge is still limited. Microbial adaptations to cold include the synthesis of cryoprotective compounds, as well as the presence of a high number of genes encoding the synthesis of proteins/enzymes characterized by a reduced proline content and highly flexible and large catalytic active sites. This study is a comparative genomic study on the adaptations of yeasts isolated from the Italian Alps, considering their growth kinetics. The optimal temperature for growth (OTG), growth rate (Gr), and draft genome sizes considerably varied (OTG, 10°C–20°C; Gr, 0.071–0.0726; genomes, 20.7–21.5 Mpb; %GC, 50.9–61.5). A direct relationship was observed between calculated protein flexibilities and OTG, but not for Gr. Putative genes encoding for cold stress response were found, as well as high numbers of genes encoding for general, oxidative, and osmotic stresses. The cold response genes found in the studied yeasts play roles in cell membrane adaptation, compatible solute accumulation, RNA structure changes, and protein folding, i.e., dihydrolipoamide dehydrogenase, glycogen synthase, omega-6 fatty acid, stearoyl-CoA desaturase, ATP-dependent RNA helicase, and elongation of very-long-chain fatty acids. A redundancy for several putative genes was found, higher for P-loop containing nucleoside triphosphate hydrolase, alpha/beta hydrolase, armadillo repeat-containing proteins, and the major facilitator superfamily protein. Hundreds of thousands of small open reading frames (SmORFs) were found in all studied yeasts, especially in Phenoliferia glacialis. Gene clusters encoding for the synthesis of secondary metabolites such as terpene, non-ribosomal peptide, and type III polyketide were predicted in four, three, and two studied yeasts, respectively.