Newly Discovered Micropeptide Regulators of SERCA Form Oligomers but Bind to the Pump As Monomers
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Requirement of the Fusogenic Micropeptide Myomixer for Muscle Formation in Zebrafish
Requirement of the fusogenic micropeptide myomixer for muscle formation in zebrafish Jun Shia,b,1, Pengpeng Bia,b,c,1, Jimin Peid, Hui Lia,b,c, Nick V. Grishind,e, Rhonda Bassel-Dubya,b,c, Elizabeth H. Chena,b,2, and Eric N. Olsona,b,c,2 aDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; bHamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; cSenator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; dHoward Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390; and eDepartment of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390 Contributed by Eric N. Olson, September 28, 2017 (sent for review August 29, 2017; reviewed by Chen-Ming Fan and Thomas A. Rando) Skeletal muscle formation requires fusion of mononucleated myo- CRISPR/Cas9, we show that myomixer is required for zebrafish blasts to form multinucleated myofibers. The muscle-specific mem- myoblast fusion. We also identify additional distantly related brane proteins myomaker and myomixer cooperate to drive myomixer orthologs from genomes of turtle and elephant shark, mammalian myoblast fusion. Whereas myomaker is highly conserved which like zebrafish myomixer can substitute for mouse myomixer across diverse vertebrate species, myomixer is a micropeptide that to promote cell fusion together with myomaker in cultured cells. shows relatively weak cross-species conservation. To explore the By comparison of amino acid sequences across these diverse functional conservation of myomixer, we investigated the expres- species, we identify a unique protein motif required for the sion and function of the zebrafish myomixer ortholog. -
The Microprotein Minion Controls Cell Fusion and Muscle Formation
ARTICLE Received 29 Mar 2017 | Accepted 19 Apr 2017 | Published 1 Jun 2017 DOI: 10.1038/ncomms15664 OPEN The microprotein Minion controls cell fusion and muscle formation Qiao Zhang1, Ajay A. Vashisht1, Jason O’Rourke1, Ste´phane Y. Corbel1, Rita Moran1, Angelica Romero1, Loren Miraglia1, Jia Zhang1, Eric Durrant1, Christian Schmedt1, Srinath C. Sampath1,2,* & Srihari C. Sampath1,2,* Although recent evidence has pointed to the existence of small open reading frame (smORF)-encoded microproteins in mammals, their function remains to be determined. Skeletal muscle development requires fusion of mononuclear progenitors to form multinucleated myotubes, a critical but poorly understood process. Here we report the identification of Minion (microprotein inducer of fusion), a smORF encoding an essential skeletal muscle specific microprotein. Myogenic progenitors lacking Minion differentiate normally but fail to form syncytial myotubes, and Minion-deficient mice die perinatally and demonstrate a marked reduction in fused muscle fibres. The fusogenic activity of Minion is conserved in the human orthologue, and co-expression of Minion and the transmembrane protein Myomaker is sufficient to induce cellular fusion accompanied by rapid cytoskeletal rearrangement, even in non-muscle cells. These findings establish Minion as a novel microprotein required for muscle development, and define a two-component programme for the induction of mammalian cell fusion. Moreover, these data also significantly expand the known functions of smORF-encoded microproteins. 1 Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA. 2 Division of Musculoskeletal Imaging, Department of Radiology, University of California San Diego School of Medicine, 200 West Arbor Drive, San Diego, California 92103, USA. -
Computational Analysis Predicts Hundreds of Coding Lncrnas in Zebrafish
biology Communication Computational Analysis Predicts Hundreds of Coding lncRNAs in Zebrafish Shital Kumar Mishra 1,2 and Han Wang 1,2,* 1 Center for Circadian Clocks, Soochow University, Suzhou 215123, China; [email protected] 2 School of Biology & Basic Medical Sciences, Medical College, Soochow University, Suzhou 215123, China * Correspondence: [email protected] or [email protected]; Tel.: +86-512-6588-2115 Simple Summary: Noncoding RNAs (ncRNAs) regulate a variety of fundamental life processes such as development, physiology, metabolism and circadian rhythmicity. RNA-sequencing (RNA- seq) technology has facilitated the sequencing of the whole transcriptome, thereby capturing and quantifying the dynamism of transcriptome-wide RNA expression profiles. However, much remains unrevealed in the huge noncoding RNA datasets that require further bioinformatic analysis. In this study, we applied six bioinformatic tools to investigate coding potentials of approximately 21,000 lncRNAs. A total of 313 lncRNAs are predicted to be coded by all the six tools. Our findings provide insights into the regulatory roles of lncRNAs and set the stage for the functional investigation of these lncRNAs and their encoded micropeptides. Abstract: Recent studies have demonstrated that numerous long noncoding RNAs (ncRNAs having more than 200 nucleotide base pairs (lncRNAs)) actually encode functional micropeptides, which likely represents the next regulatory biology frontier. Thus, identification of coding lncRNAs from ever-increasing lncRNA databases would be a bioinformatic challenge. Here we employed the Coding Potential Alignment Tool (CPAT), Coding Potential Calculator 2 (CPC2), LGC web server, Citation: Mishra, S.K.; Wang, H. Coding-Non-Coding Identifying Tool (CNIT), RNAsamba, and MicroPeptide identification tool Computational Analysis Predicts (MiPepid) to analyze approximately 21,000 zebrafish lncRNAs and computationally to identify Hundreds of Coding lncRNAs in 2730–6676 zebrafish lncRNAs with high coding potentials, including 313 coding lncRNAs predicted Zebrafish. -
Stem Cell Metabolic and Epigenetic Reprogramming
RESEARCH HIGHLIGHTS Cell 16, 39–50, 2015). They discovered that inactivating Rb facilitates Enhancer evolution in mammals reprogramming of fibroblasts to a pluripotent state. Surprisingly, their Widespread changes in regulatory genomic regions have data indicate that this does not involve interference with the cell cycle but underpinned mammalian evolution, but our knowledge about instead that Rb directly binds to and represses pluripotency-associated these regions is still incomplete. Paul Flicek, Duncan Odom and loci such as Oct4 (Pou5f1) and Sox2. Loss of Rb seems to compensate colleagues have now contributed to a better understanding of for the omission of Sox2 from the cocktail of reprogramming factors. how the noncoding portions of mammalian genomes have been Furthermore, genetic disruption of Sox2 precludes tumor formation in reshaped over the last 180 million years (Cell 160, 554–566, mice lacking functional Rb protein. This study positions Rb as a repres- 2015). They characterized active promoters and enhancers in sor of the pluripotency gene regulatory network and suggests that loss of liver samples from 20 mammalian species—from Tasmanian Rb might clear the path for Sox2, or other master regulators of stem cell devil to human—by examining the genome-wide enrichment identity, to induce cancer. It will be interesting to analyze the potential profiles of H3K4me3 and H3K27ac, two histone modifications role of Rb in other types of in vitro reprogramming. TF associated with transcriptional activity. Their analyses suggest that rapid enhancer evolution and high promoter conservation are fundamental traits of mammalian genomes. Intriguingly, they Micropeptide regulates muscle performance find that the majority of newly evolved enhancers originated via It is becoming increasingly recognized that some transcripts anno- functional exaptation of ancestral DNA and not through clade- tated as long noncoding RNAs (lncRNAs) contain short ORFs that specific expansions of repeat elements. -
The Lncrna Toolkit: Databases and in Silico Tools for Lncrna Analysis
non-coding RNA Review The lncRNA Toolkit: Databases and In Silico Tools for lncRNA Analysis Holly R. Pinkney † , Brandon M. Wright † and Sarah D. Diermeier * Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand; [email protected] (H.R.P.); [email protected] (B.M.W.) * Correspondence: [email protected] † These authors contributed equally to this work. Received: 29 November 2020; Accepted: 15 December 2020; Published: 16 December 2020 Abstract: Long non-coding RNAs (lncRNAs) are a rapidly expanding field of research, with many new transcripts identified each year. However, only a small subset of lncRNAs has been characterized functionally thus far. To aid investigating the mechanisms of action by which new lncRNAs act, bioinformatic tools and databases are invaluable. Here, we review a selection of computational tools and databases for the in silico analysis of lncRNAs, including tissue-specific expression, protein coding potential, subcellular localization, structural conformation, and interaction partners. The assembled lncRNA toolkit is aimed primarily at experimental researchers as a useful starting point to guide wet-lab experiments, mainly containing multi-functional, user-friendly interfaces. With more and more new lncRNA analysis tools available, it will be essential to provide continuous updates and maintain the availability of key software in the future. Keywords: non-coding RNAs; long non-coding RNAs; databases; computational analysis; bioinformatic prediction software; RNA interactions; coding potential; RNA structure; RNA function 1. Introduction For decades, the human genome was thought to be a desert of ‘junk DNA’ with sporadic oases of transcriptionally active genes, most of them coding for proteins. -
Coding Sequences of Sarcoplasmic Reticulum Calcium Atpase Regulatory Peptides and Expression of Calcium Regulatory Genes in Recurrent Exertional Rhabdomyolysis
University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Faculty Papers and Publications in Animal Science Animal Science Department 2019 Coding sequences of sarcoplasmic reticulum calcium ATPase regulatory peptides and expression of calcium regulatory genes in recurrent exertional rhabdomyolysis Stephanie J. Valberg Kaitlin Soave Zoe J. Williams Sudeep Perumbakkam Melissa Schott See next page for additional authors Follow this and additional works at: https://digitalcommons.unl.edu/animalscifacpub Part of the Genetics and Genomics Commons, and the Meat Science Commons This Article is brought to you for free and open access by the Animal Science Department at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Faculty Papers and Publications in Animal Science by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Authors Stephanie J. Valberg, Kaitlin Soave, Zoe J. Williams, Sudeep Perumbakkam, Melissa Schott, Carrie J. Finno, Jessica L. Petersen, Clara Fenger, Joseph M. Autry, and David D. Thomas Received: 7 August 2018 Accepted: 11 January 2019 DOI: 10.1111/jvim.15425 STANDARD ARTICLE Coding sequences of sarcoplasmic reticulum calcium ATPase regulatory peptides and expression of calcium regulatory genes in recurrent exertional rhabdomyolysis Stephanie J. Valberg1 | Kaitlin Soave1 | Zoë J. Williams1 | Sudeep Perumbakkam1 | Melissa Schott1 | Carrie J. Finno2 | Jessica L. Petersen3 | Clara Fenger4 | Joseph M. Autry5 | David D. Thomas5 1McPhail Equine Performance Center, Department of Large Animal Clinical Sciences, Background: Sarcolipin (SLN), myoregulin (MRLN), and dwarf open reading frame (DWORF) are Michigan State University, East Lansing, transmembrane regulators of the sarcoplasmic reticulum calcium transporting ATPase (SERCA) Michigan that we hypothesized played a role in recurrent exertional rhabdomyolysis (RER). -
Allosteric Regulation of SERCA by Phosphorylation- Mediated Conformational Shift of Phospholamban
Allosteric regulation of SERCA by phosphorylation- mediated conformational shift of phospholamban Martin Gustavssona, Raffaello Verardia, Daniel G. Mullena, Kaustubh R. Moteb, Nathaniel J. Traasetha,1, T. Gopinatha, and Gianluigi Vegliaa,b,2 aDepartment of Biochemistry, Molecular Biology, and Biophysics and bDepartment of Chemistry, University of Minnesota, Minneapolis, MN 55455 Edited by Chikashi Toyoshima, University of Tokyo, Tokyo, Japan, and approved September 13, 2013 (received for review May 26, 2013) The membrane protein complex between the sarcoplasmic re- cytoplasmic domain binds SERCA’s N domain in an α-helical + ticulum Ca2 -ATPase (SERCA) and phospholamban (PLN) controls conformation, suggesting that the inhibitory effect may be eli- + Ca2 transport in cardiomyocytes, thereby modulating cardiac con- cited via an induced fit mechanism. tractility. β-Adrenergic-stimulated phosphorylation of PLN at Ser- Interestingly, PLN’s cytoplasmic domain in the recent X-ray 16 enhances SERCA activity via an unknown mechanism. Using structure of the complex is completely unresolved (8), leaving solid-state nuclear magnetic resonance spectroscopy, we mapped many questions regarding its regulatory function unanswered. the physical interactions between SERCA and both unphosphory- Moreover, there have been few structural data on the complex lated and phosphorylated PLN in membrane bilayers. We found between SERCA and phosphorylated PLN. On the basis of cross- that the allosteric regulation of SERCA depends on the conforma- linking and sparse -
Minireview: Novel Micropeptide Discovery by Proteomics and Deep Sequencing Methods
fgene-12-651485 May 6, 2021 Time: 11:28 # 1 MINI REVIEW published: 06 May 2021 doi: 10.3389/fgene.2021.651485 Minireview: Novel Micropeptide Discovery by Proteomics and Deep Sequencing Methods Ravi Tharakan1* and Akira Sawa2,3 1 National Institute on Aging, National Institutes of Health, Baltimore, MD, United States, 2 Departments of Psychiatry, Neuroscience, Biomedical Engineering, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 3 Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States A novel class of small proteins, called micropeptides, has recently been discovered in the genome. These proteins, which have been found to play important roles in many physiological and cellular systems, are shorter than 100 amino acids and were overlooked during previous genome annotations. Discovery and characterization of more micropeptides has been ongoing, often using -omics methods such as proteomics, RNA sequencing, and ribosome profiling. In this review, we survey the recent advances in the micropeptides field and describe the methodological and Edited by: conceptual challenges facing future micropeptide endeavors. Liangliang Sun, Keywords: micropeptides, miniproteins, proteogenomics, sORF, ribosome profiling, proteomics, genomics, RNA Michigan State University, sequencing United States Reviewed by: Yanbao Yu, INTRODUCTION J. Craig Venter Institute (Rockville), United States The sequencing and publication of complete genomic sequences of many organisms have aided Hongqiang Qin, the medical sciences greatly, allowing advances in both human genetics and the biology of human Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China disease, as well as a greater understanding of the biology of human pathogens (Firth and Lipkin, 2013). -
Micropeptide Regulates Muscle Performance
RESEARCH HIGHLIGHTS Cell 16, 39–50, 2015). They discovered that inactivating Rb facilitates Enhancer evolution in mammals reprogramming of fibroblasts to a pluripotent state. Surprisingly, their Widespread changes in regulatory genomic regions have data indicate that this does not involve interference with the cell cycle but underpinned mammalian evolution, but our knowledge about instead that Rb directly binds to and represses pluripotency-associated these regions is still incomplete. Paul Flicek, Duncan Odom and loci such as Oct4 (Pou5f1) and Sox2. Loss of Rb seems to compensate colleagues have now contributed to a better understanding of for the omission of Sox2 from the cocktail of reprogramming factors. how the noncoding portions of mammalian genomes have been Furthermore, genetic disruption of Sox2 precludes tumor formation in reshaped over the last 180 million years (Cell 160, 554–566, mice lacking functional Rb protein. This study positions Rb as a repres- 2015). They characterized active promoters and enhancers in sor of the pluripotency gene regulatory network and suggests that loss of liver samples from 20 mammalian species—from Tasmanian Rb might clear the path for Sox2, or other master regulators of stem cell devil to human—by examining the genome-wide enrichment identity, to induce cancer. It will be interesting to analyze the potential profiles of H3K4me3 and H3K27ac, two histone modifications role of Rb in other types of in vitro reprogramming. TF associated with transcriptional activity. Their analyses suggest that rapid enhancer evolution and high promoter conservation are fundamental traits of mammalian genomes. Intriguingly, they Micropeptide regulates muscle performance find that the majority of newly evolved enhancers originated via It is becoming increasingly recognized that some transcripts anno- functional exaptation of ancestral DNA and not through clade- tated as long noncoding RNAs (lncRNAs) contain short ORFs that specific expansions of repeat elements. -
2790.Full.Pdf
Published OnlineFirst March 13, 2020; DOI: 10.1158/0008-5472.CAN-19-3440 CANCER RESEARCH | MOLECULAR CELL BIOLOGY A Novel Micropeptide Encoded by Y-Linked LINC00278 Links Cigarette Smoking and AR Signaling in Male Esophageal Squamous Cell Carcinoma Siqi Wu1, Liyuan Zhang2, Jieqiong Deng1, Binbin Guo1, Fang Li1, Yirong Wang1, Rui Wu1, Shenghua Zhang1, Jiachun Lu3, and Yifeng Zhou1 ABSTRACT ◥ Long noncoding RNAs (lncRNA) have been shown to play critical Graphical Abstract: http://cancerres.aacrjournals.org/content/ roles in many diseases, including esophageal squamous cell carcino- canres/80/13/2790/F1.large.jpg. ma (ESCC). Recent studies have reported that some lncRNA encode See related commentary by Banday et al., p. 2718 functional micropeptides. However, the association between ESCC and micropeptides encoded by lncRNA remains largely unknown. In this study, we characterized a Y-linked lncRNA, LINC00278,which was downregulated in male ESCC. LINC00278 encoded a Yin Yang 1 Chr.Y (YY1)-binding micropeptide, designated YY1BM. YY1BM was LINC0027 involved in the ESCC progression and inhibited the interaction 8 sORF A A METTL3 A between YY1 and androgen receptor (AR), which in turn decreased METTL14 eEF2K ALKBH5 eEF2K eEF2K expression of through the AR signaling pathway. Down- AR YY1 regulation of YY1BM significantly upregulated eEF2K expression WTAP m6A Smoking and inhibited apoptosis, thus conferring ESCC cells more adaptive to LINC00278 sORF A A nutrient deprivation. Cigarette smoking decreased m6A modification A eEF2 of LINC00278 and YY1BM translation. In conclusion, these results YTHDF1 provide a novel mechanistic link between cigarette smoking and AR YY1BM Translation Caspase-3 signaling in male ESCC progression. -
Conserved Luminal C-Terminal Domain Dynamically Controls Interdomain Communication in Sarcolipin
bioRxiv preprint doi: https://doi.org/10.1101/2020.03.28.013425; this version posted July 7, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Conserved luminal C-terminal domain dynamically controls interdomain communication in sarcolipin Rodrigo Aguayo-Ortiz, Eli Fernández-de Gortari, and L. Michel Espinoza-Fonseca* Center for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA ABSTRACT: Sarcolipin (SLN) mediates Ca2+ transport and metabolism in muscle by regulating the activity of the Ca2+ pump SERCA. SLN has a conserved luminal C-terminal domain that contributes to the its functional divergence among homologous SERCA regulators, but the precise mechanistic role of this domain remains poorly understood. We used all- atom molecular dynamics (MD) simulations of SLN totaling 77.5 µs to show that the N- (NT) and C-terminal (CT) domains function in concert. Analysis of the MD simulations showed that serial deletions of SLN C-terminus does not affect the stability of the peptide nor induce dissociation of SLN from the membrane but promotes a gradual decrease in both tilt angle of the transmembrane helix and the local thickness of the lipid bilayer. Mutual information analysis showed that the NT and CT domains communicate with each other in SLN, and that interdomain communication is partially or completely abolished upon deletion of the conserved segment Tyr29-Tyr31 as well as by serial deletions beyond this domain. -
Fusogenic Micropeptide Myomixer Is Essential for Satellite Cell Fusion and Muscle Regeneration
Fusogenic micropeptide Myomixer is essential for satellite cell fusion and muscle regeneration Pengpeng Bia,b,c, John R. McAnallya,b,c, John M. Sheltond, Efrain Sánchez-Ortiza,b,c, Rhonda Bassel-Dubya,b,c, and Eric N. Olsona,b,c,1 aDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; bHamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; cSenator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390; and dDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390 Contributed by Eric N. Olson, March 1, 2018 (sent for review January 3, 2018; reviewed by Bradley B. Olwin and Nadia A. Rosenthal) Regeneration of skeletal muscle in response to injury occurs through fusion and muscle formation during embryogenesis in mice and fusion of a population of stem cells, known as satellite cells, with zebrafish (14, 16–20). Myomaker is also required for fusion of injured myofibers. Myomixer, a muscle-specific membrane micro- SCs during adult muscle regeneration (21). peptide, cooperates with the transmembrane protein Myomaker Myomaker and Myomixer are up-regulated in SCs during to regulate embryonic myoblast fusion and muscle formation. To muscle regeneration (14, 16, 17, 21). However, the perinatal investigate the role of Myomixer in muscle regeneration, we used lethality of Myomixer null mice has precluded an analysis of its CRISPR/Cas9-mediated genome editing to generate conditional potential involvement in myofiber regeneration in response to knockout Myomixer alleles in mice. We show that genetic deletion injury (14).