{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T14:07:47Z","timestamp":1740146867682,"version":"3.37.3"},"reference-count":116,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009973","name":"California State University Channel Islands","doi-asserted-by":"publisher","award":["Research, Scholarship and Creative Activity Grant #811-GD970"],"award-info":[{"award-number":["Research, Scholarship and Creative Activity Grant #811-GD970"]}],"id":[{"id":"10.13039\/100009973","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009973","name":"California State University Channel Islands","doi-asserted-by":"publisher","award":["Faculty Research and Development Minigrant"],"award-info":[{"award-number":["Faculty Research and Development Minigrant"]}],"id":[{"id":"10.13039\/100009973","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009973","name":"California State University Channel Islands","doi-asserted-by":"publisher","award":["Student Research Steering Council Microgrant"],"award-info":[{"award-number":["Student Research Steering Council Microgrant"]}],"id":[{"id":"10.13039\/100009973","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009973","name":"California State University Channel Islands","doi-asserted-by":"publisher","award":["Provost\u2019s Faculty Resource Fund Grant #GD945"],"award-info":[{"award-number":["Provost\u2019s Faculty Resource Fund Grant #GD945"]}],"id":[{"id":"10.13039\/100009973","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009973","name":"California State University Channel Islands","doi-asserted-by":"publisher","award":["Instructional funding for Independent Research (Bio 494)"],"award-info":[{"award-number":["Instructional funding for Independent Research (Bio 494)"]}],"id":[{"id":"10.13039\/100009973","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Cetacea and other diving mammals have undergone numerous adaptations to their aquatic environment, among them high levels of the oxygen-carrying intracellular hemoprotein myoglobin in skeletal muscles. Hypotheses regarding the mechanisms leading to these high myoglobin levels often invoke the induction of gene expression by exercise, hypoxia, and other physiological gene regulatory pathways. Here we explore an alternative hypothesis: that cetacean myoglobin genes have evolved high levels of transcription driven by the intrinsic developmental mechanisms that drive muscle cell differentiation. We have used luciferase assays in differentiated C2C12 cells to test this hypothesis. Contrary to our hypothesis, we find that the myoglobin gene from the minke whale, <jats:italic>Balaenoptera acutorostrata<\/jats:italic>, shows a low level of expression, only about 8% that of humans. This low expression level is broadly shared among cetaceans and artiodactylans. Previous work on regulation of the human gene has identified a core muscle-specific enhancer comprised of two regions, the \u201cAT element\u201d and a C-rich sequence 5\u2019 of the AT element termed the \u201cCCAC-box\u201d. Analysis of the minke whale gene supports the importance of the AT element, but the minke whale CCAC-box ortholog has little effect. Instead, critical positive input has been identified in a G-rich region 3\u2019 of the AT element. Also, a conserved E-box in exon 1 positively affects expression, despite having been assigned a repressive role in the human gene. Last, a novel region 5\u2019 of the core enhancer has been identified, which we hypothesize may function as a boundary element. These results illustrate regulatory flexibility during evolution. We discuss the possibility that low transcription levels are actually beneficial, and that evolution of the myoglobin protein toward enhanced stability is a critical factor in the accumulation of high myoglobin levels in adult cetacean muscle tissue.<\/jats:p>","DOI":"10.1371\/journal.pone.0284834","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T17:53:04Z","timestamp":1693331584000},"page":"e0284834","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative analysis of the myoglobin gene in whales and humans reveals evolutionary changes in regulatory elements and expression levels"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5734-5763","authenticated-orcid":true,"given":"Charles","family":"Sackerson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Medina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Maldonado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Daly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Cartwright","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"pone.0284834.ref001","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1007\/s12052-009-0135-2","article-title":"From land to water: the origin of whales, dolphins, and porpoises.","volume":"2","author":"JGM Thewissen","year":"2009","journal-title":"Evol Edu Outreach."},{"key":"pone.0284834.ref002","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev-earth-040809-152453","article-title":"The origin (s) of whales.","volume":"38","author":"MD Uhen","year":"2010","journal-title":"Annu Rev Earth Planet Sci"},{"issue":"1699","key":"pone.0284834.ref003","doi-asserted-by":"crossref","first-page":"20150140","DOI":"10.1098\/rstb.2015.0140","article-title":"Mammal madness: is the mammal tree of life not yet resolved","volume":"371","author":"NM Foley","year":"2016","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"pone.0284834.ref004","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1146\/annurev.physiol.60.1.19","article-title":"The physiological basis of diving to depth: birds and mammals","volume":"60","author":"GL Kooyman","year":"1998","journal-title":"Annu Rev Physiol"},{"issue":"Pt 20","key":"pone.0284834.ref005","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1242\/jeb.01172","article-title":"Myoglobin: an essential hemoprotein in striated muscle","volume":"207","author":"GA Ordway","year":"2004","journal-title":"J Exp Biol"},{"key":"pone.0284834.ref006","doi-asserted-by":"crossref","first-page":"732190","DOI":"10.3389\/fendo.2021.732190","article-title":"Myoglobin Protects Breast Cancer Cells Due to Its ROS and NO Scavenging Properties.","volume":"12","author":"T Quinting","year":"2021","journal-title":"Front Endocrinol (Lausanne)."},{"issue":"2","key":"pone.0284834.ref007","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1113\/JP270824","article-title":"Myoglobin and the regulation of mitochondrial respiratory chain complex IV","volume":"594","author":"T Yamada","journal-title":"J Physiol"},{"issue":"1","key":"pone.0284834.ref008","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1002\/cphy.c091003","article-title":"Diving mammals.","volume":"1","author":"PJ Ponganis","year":"2011","journal-title":"Compr Physiol."},{"issue":"6","key":"pone.0284834.ref009","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1016\/j.cell.2011.02.017","article-title":"Evolution of gene regulatory networks controlling body plan development","volume":"144","author":"IS Peter","year":"2011","journal-title":"Cell"},{"issue":"12","key":"pone.0284834.ref010","doi-asserted-by":"crossref","first-page":"e1003995","DOI":"10.1371\/journal.pgen.1003995","article-title":"Contributions of protein-coding and regulatory change to adaptive molecular evolution in murid rodents","volume":"9","author":"DL Halligan","year":"2013","journal-title":"PLoS Genet"},{"issue":"Suppl 1","key":"pone.0284834.ref011","first-page":"8605","article-title":"Emerging principles of regulatory evolution","volume":"1","author":"B Prud\u2019homme","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pone.0284834.ref012","doi-asserted-by":"crossref","first-page":"e0145893","DOI":"10.1371\/journal.pone.0145893","article-title":"Tracking the Development of Muscular Myoglobin Stores in Mysticete Calves.","volume":"11","author":"R Cartwright","year":"2016","journal-title":"PLoS One"},{"issue":"23","key":"pone.0284834.ref013","doi-asserted-by":"crossref","first-page":"13896","DOI":"10.1016\/S0021-9258(18)80084-9","article-title":"Identification of a muscle-specific enhancer within the 5\u2019-flanking region of the human myoglobin gene","volume":"264","author":"BH Devlin","year":"1989","journal-title":"J Biol Chem"},{"issue":"11","key":"pone.0284834.ref014","first-page":"5024","article-title":"A 40-kilodalton protein binds specifically to an upstream sequence element essential for muscle-specific transcription of the human myoglobin promoter","volume":"12","author":"R Bassel-Duby","year":"1992","journal-title":"Mol Cell Biol"},{"issue":"2","key":"pone.0284834.ref015","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1161\/01.RES.73.2.360","article-title":"Sequence elements required for transcriptional activity of the human myoglobin promoter in intact myocardium","volume":"73","author":"R Bassel-Duby","year":"1993","journal-title":"Circ Res"},{"issue":"3","key":"pone.0284834.ref016","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/(SICI)1097-4644(19980901)70:3<366::AID-JCB10>3.0.CO;2-J","article-title":"Collaborative interactions between MEF-2 and Sp1 in muscle-specific gene regulation","volume":"70","author":"J Grayson","year":"1998","journal-title":"J Cell Biochem"},{"issue":"Pt 16","key":"pone.0284834.ref017","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1242\/jeb.041442","article-title":"Regulation of myoglobin expression","volume":"213","author":"SB Kanatous","year":"2010","journal-title":"J Exp Biol"},{"issue":"4","key":"pone.0284834.ref018","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1128\/MCB.15.4.1870","article-title":"Synergistic interactions between heterologous upstream activation elements and specific TATA sequences in a muscle-specific promoter","volume":"15","author":"J Grayson","year":"1995","journal-title":"Mol Cell Biol"},{"volume-title":"Nucleotide","year":"1988","key":"pone.0284834.ref019"},{"issue":"D1","key":"pone.0284834.ref020","doi-asserted-by":"crossref","first-page":"D1115","DOI":"10.1093\/nar\/gkab959","article-title":"The UCSC Genome Browser database: 2022 update.","volume":"50","author":"BT Lee","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"7414","key":"pone.0284834.ref021","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nature11232","article-title":"The accessible chromatin landscape of the human genome","volume":"489","author":"RE Thurman","year":"2012","journal-title":"Nature"},{"issue":"22","key":"pone.0284834.ref022","doi-asserted-by":"crossref","first-page":"6414","DOI":"10.1093\/emboj\/20.22.6414","article-title":"Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway","volume":"20","author":"H Wu","year":"2001","journal-title":"EMBO J"},{"issue":"3","key":"pone.0284834.ref023","doi-asserted-by":"crossref","first-page":"C393","DOI":"10.1152\/ajpcell.00428.2008","article-title":"Hypoxia reprograms calcium signaling and regulates myoglobin expression","volume":"296","author":"SB Kanatous","year":"2009","journal-title":"Am J Physiol Cell Physiol"},{"issue":"8","key":"pone.0284834.ref024","doi-asserted-by":"crossref","first-page":"102920","DOI":"10.1016\/j.isci.2021.102920","article-title":"Common and unique strategies of myoglobin evolution for deep-sea adaptation of diving mammals","volume":"24","author":"Y Isogai","year":"2021","journal-title":"iScience"},{"key":"pone.0284834.ref025","doi-asserted-by":"crossref","first-page":"110843","DOI":"10.1016\/j.cbpa.2020.110843","article-title":"The role of myoglobin in the evolution of mammalian diving capacity\u2014The August Krogh principle applied in molecular and evolutionary physiology","volume":"252","author":"M. Berenbrink","year":"2021","journal-title":"Comp Biochem Physiol A Mol Integr Physiol"},{"issue":"3","key":"pone.0284834.ref026","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S1050-1738(02)00256-6","article-title":"Emerging roles for myoglobin in the heart","volume":"13","author":"DJ Garry","year":"2003","journal-title":"Trends Cardiovasc Med"},{"issue":"20","key":"pone.0284834.ref027","doi-asserted-by":"crossref","first-page":"17361","DOI":"10.1074\/jbc.M101251200","article-title":"Regulatory elements governing transcription in specialized myofiber subtypes","volume":"276","author":"Z Yan","year":"2001","journal-title":"J Biol Chem"},{"key":"pone.0284834.ref028","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.1016\/S0092-8674(02)00699-2","article-title":"NFAT signaling: choreographing the social lives of cells","volume":"109","author":"GR Crabtree","year":"2002","journal-title":"Cell"},{"issue":"2","key":"pone.0284834.ref029","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/0167-4781(94)90001-9","article-title":"Structure and function of helix-loop-helix proteins","volume":"1218","author":"C Murre","year":"1994","journal-title":"Biochim Biophys Acta"},{"issue":"40","key":"pone.0284834.ref030","doi-asserted-by":"crossref","first-page":"23246","DOI":"10.1074\/jbc.270.40.23246","article-title":"Determination of the consensus binding site for MEF2 expressed in muscle and brain reveals tissue-specific sequence constraints","volume":"270","author":"V Andr\u00e9s","year":"1995","journal-title":"J Biol Chem"},{"issue":"7","key":"pone.0284834.ref031","first-page":"4596","article-title":"Myocyte nuclear factor, a novel winged-helix transcription factor under both developmental and neural regulation in striated myocytes","volume":"14","author":"R Bassel-Duby","year":"1994","journal-title":"Mol Cell Biol"},{"issue":"16","key":"pone.0284834.ref032","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1101\/gad.12.16.2499","article-title":"A calcineurin-dependent transcriptional pathway controls skeletal muscle fiber type","volume":"12","author":"ER Chin","year":"1998","journal-title":"Genes Dev"},{"issue":"9","key":"pone.0284834.ref033","doi-asserted-by":"crossref","first-page":"4125","DOI":"10.1007\/s00018-021-03776-z","article-title":"GAGA factor: a multifunctional pioneering chromatin protein","volume":"78","author":"D Chetverina","year":"2021","journal-title":"Cell Mol Life Sci"},{"issue":"1","key":"pone.0284834.ref034","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s12915-017-0411-5","article-title":"Biological function in the twilight zone of sequence conservation.","volume":"15","author":"CP Ponting","year":"2017","journal-title":"BMC Biol."},{"issue":"9","key":"pone.0284834.ref035","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0168-9525(00)02081-3","article-title":"Conserved noncoding sequences are reliable guides to regulatory elements","volume":"16","author":"RC Hardison","year":"2000","journal-title":"Trends Genet"},{"issue":"3","key":"pone.0284834.ref036","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1101\/gr.1961204","article-title":"Noncoding sequences conserved in a limited number of mammals in the SIM2 interval are frequently functional","volume":"14","author":"KA Frazer","year":"2004","journal-title":"Genome Res"},{"issue":"1","key":"pone.0284834.ref037","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1159\/000078011","article-title":"Interspecies comparison of neuroglobin, cytoglobin and myoglobin: sequence evolution and candidate regulatory elements","volume":"105","author":"S Wystub","year":"2004","journal-title":"Cytogenet Genome Res"},{"issue":"36","key":"pone.0284834.ref038","doi-asserted-by":"crossref","first-page":"19259","DOI":"10.1016\/S0021-9258(19)77625-X","article-title":"The formation and function of DNase I hypersensitive sites in the process of gene activation","volume":"263","author":"SC Elgin","year":"1988","journal-title":"J Biol Chem"},{"issue":"1620","key":"pone.0284834.ref039","doi-asserted-by":"crossref","first-page":"20120369","DOI":"10.1098\/rstb.2012.0369","article-title":"CTCF: the protein, the binding partners, the binding sites and their chromatin loops","volume":"368","author":"SJ Holwerda","year":"2013","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"issue":"1","key":"pone.0284834.ref040","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/gt.2011.70","article-title":"CTF\/NF1 transcription factors act as potent genetic insulators for integrating gene transfer vectors","volume":"19","author":"A Gaussin","year":"2012","journal-title":"Gene Ther"},{"issue":"7414","key":"pone.0284834.ref041","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome.","volume":"489","author":"ENCODE Project Consortium","year":"2012","journal-title":"Nature"},{"issue":"2","key":"pone.0284834.ref042","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S1095-6433(00)00182-3","article-title":"Body size and skeletal muscle myoglobin of cetaceans: adaptations for maximizing dive duration","volume":"126","author":"SR Noren","year":"2000","journal-title":"Comp Biochem Physiol A Mol Integr Physiol"},{"issue":"4","key":"pone.0284834.ref043","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nrg3185","article-title":"Insights into the regulation of protein abundance from proteomic and transcriptomic analyses","volume":"13","author":"C Vogel","year":"2012","journal-title":"Nat Rev Genet"},{"issue":"8","key":"pone.0284834.ref044","doi-asserted-by":"crossref","first-page":"4791","DOI":"10.1093\/nar\/gku126","article-title":"Transcript level and sequence determinants of protein abundance and noise in Escherichia coli","volume":"42","author":"JC Guimaraes","year":"2014","journal-title":"Nucleic Acids Res"},{"issue":"12","key":"pone.0284834.ref045","first-page":"4539","article-title":"Myoglobin expression: early induction and subsequent modulation of myoglobin and myoglobin mRNA during myogenesis","volume":"6","author":"PA Weller","year":"1986","journal-title":"Mol Cell Biol"},{"issue":"12","key":"pone.0284834.ref046","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.3390\/ani11123599","article-title":"Prediction and Experimental Verification of a Hierarchical Transcription Factor Regulatory Network of Porcine Myoglobin (Mb).","volume":"11","author":"D Yuan","year":"2021","journal-title":"Animals (Basel)."},{"issue":"4","key":"pone.0284834.ref047","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s004210050519","article-title":"Maintenance of myoglobin concentration in human skeletal muscle after heavy resistance training","volume":"79","author":"K Masuda","year":"1999","journal-title":"Eur J Appl Physiol Occup Physiol"},{"key":"pone.0284834.ref048","doi-asserted-by":"crossref","first-page":"1726","DOI":"10.1073\/pnas.90.5.1726","article-title":"Gradients of transgene expression directed by the human myoglobin promoter in the developing mouse heart","volume":"90","author":"W. J. Parsons","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"pone.0284834.ref049","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1533\/9781908818652.9","article-title":"Model Systems","author":"M. Montano","year":"2014","journal-title":". Translational Biology in Medicine"},{"issue":"6 Pt 1","key":"pone.0284834.ref050","doi-asserted-by":"crossref","first-page":"C1795","DOI":"10.1152\/ajpcell.1994.266.6.C1795","article-title":"C2C12 cells: biophysical, biochemical, and immunocytochemical properties","volume":"266","author":"DK McMahon","year":"1994","journal-title":"Am J Physiol"},{"issue":"3","key":"pone.0284834.ref051","first-page":"223","article-title":"C2C12 murine myoblasts as a model of skeletal muscle development: morpho-functional characterization","volume":"48","author":"S Burattini","year":"2004","journal-title":"Eur J Histochem"},{"key":"pone.0284834.ref052","doi-asserted-by":"crossref","first-page":"44570","DOI":"10.1038\/srep44570","article-title":"In vitro drug testing based on contractile activity of C2C12 cells in an epigenetic drug model.","volume":"7","author":"K Ikeda","year":"2017","journal-title":"Sci Rep."},{"issue":"2","key":"pone.0284834.ref053","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1152\/physiolgenomics.00093.2011","article-title":"Analysis of early C2C12 myogenesis identifies stably and differentially expressed transcriptional regulators whose knock-down inhibits myoblast differentiation","volume":"44","author":"S Rajan","year":"2012","journal-title":"Physiol Genomics"},{"issue":"3","key":"pone.0284834.ref054","doi-asserted-by":"crossref","first-page":"C615","DOI":"10.1152\/ajpcell.00540.2019","article-title":"Comparative profiling of skeletal muscle models reveals heterogeneity of transcriptome and metabolism","volume":"318","author":"AM Abdelmoez","year":"2020","journal-title":"Am J Physiol Cell Physiol"},{"issue":"12","key":"pone.0284834.ref055","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1242\/dev.151035","article-title":"Making muscle: skeletal myogenesis in vivo and in vitro","volume":"144","author":"J Chal","year":"2017","journal-title":"Development"},{"issue":"3","key":"pone.0284834.ref056","doi-asserted-by":"crossref","first-page":"C390","DOI":"10.1152\/ajpcell.00002.2009","article-title":"Both hypoxia and work are required to enhance expression of myoglobin in skeletal muscle. Focus on \"Hypoxia reprograms calcium signaling and regulates myoglobin expression\".","volume":"296","author":"BA Wittenberg","year":"2009","journal-title":"Am J Physiol Cell Physiol"},{"issue":"2","key":"pone.0284834.ref057","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1042\/BJ20090716","article-title":"Nitric oxide stimulates myoglobin gene and protein expression in vascular smooth muscle","volume":"423","author":"BS Rayner","year":"2009","journal-title":"Biochem J"},{"issue":"3","key":"pone.0284834.ref058","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1023\/A:1026328203526","article-title":"Lactation in whales and dolphins: evidence of divergence between baleen- and toothed-species.","volume":"2","author":"OT Oftedal","year":"1997","journal-title":"J Mammary Gland Biol Neoplasia"},{"key":"pone.0284834.ref059","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1748-7692.2007.00165.x","article-title":"Variation in blubber fatty acid composition among marine mammals in the Canadian Arctic.","volume":"24","author":"GW Thiemann","year":"2008","journal-title":"Mar Mammal Sci"},{"key":"pone.0284834.ref060","doi-asserted-by":"crossref","first-page":"icad011","DOI":"10.1093\/icb\/icad011","article-title":"Building Cetacean Locomotor Muscles Throughout Ontogeny to Support High Performance Swimming into Adulthood","author":"SR Noren","year":"2023","journal-title":"Integr Comp Biol."},{"issue":"2","key":"pone.0284834.ref061","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1086\/707538","article-title":"Extremely Elevated Myoglobin Contents in the Pelagic Melon-Headed Whale (Peponocephala electra) after Prolonged Postnatal Maturation.","volume":"93","author":"SR Noren","year":"2020","journal-title":"Physiol Biochem Zool"},{"issue":"1","key":"pone.0284834.ref062","doi-asserted-by":"crossref","first-page":"16883","DOI":"10.1038\/s41598-018-34984-6","article-title":"Tracing whale myoglobin evolution by resurrecting ancient proteins","volume":"8","author":"Y Isogai","year":"2018","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0284834.ref063","doi-asserted-by":"crossref","first-page":"e1002929","DOI":"10.1371\/journal.pcbi.1002929","article-title":"Positively selected sites in cetacean myoglobins contribute to protein stability.","volume":"9","author":"P Dasmeh","year":"2013","journal-title":"PLoS Comput Biol."},{"issue":"6138","key":"pone.0284834.ref064","doi-asserted-by":"crossref","first-page":"1234192","DOI":"10.1126\/science.1234192","article-title":"Evolution of mammalian diving capacity traced by myoglobin net surface charge","volume":"340","author":"S Mirceta","year":"2013","journal-title":"Science"},{"issue":"15","key":"pone.0284834.ref065","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1021\/acs.biochem.2c00166","article-title":"Improvement of Protein Solubility in Macromolecular Crowding during Myoglobin Evolution","volume":"61","author":"Y Isogai","journal-title":"Biochemistry"},{"issue":"32","key":"pone.0284834.ref066","doi-asserted-by":"crossref","first-page":"7581","DOI":"10.1002\/chem.201900178","article-title":"What Are We Missing by Not Measuring the Net Charge of Proteins?","volume":"25","author":"CT Zahler","journal-title":"Chemistry"},{"issue":"3","key":"pone.0284834.ref067","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.molcel.2009.04.026","article-title":"A role for ubiquitin in selective autophagy","volume":"34","author":"V Kirkin","year":"2009","journal-title":"Mol Cell"},{"issue":"2","key":"pone.0284834.ref068","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1042\/bj0550298","article-title":"The activity of the cytochrome system in muscle and its relation to myoglobin","volume":"55","author":"RA Lawrie","year":"1953","journal-title":"Biochem J"},{"issue":"1","key":"pone.0284834.ref069","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.abb.2005.01.016","article-title":"On the difference in stability between horse and sperm whale myoglobins","volume":"436","author":"WC Regis","year":"2005","journal-title":"Arch Biochem Biophys"},{"issue":"35","key":"pone.0284834.ref070","doi-asserted-by":"crossref","first-page":"27129","DOI":"10.1016\/S0021-9258(19)61489-4","article-title":"The stabilities of mammalian apomyoglobins vary over a 600-fold range and can be enhanced by comparative mutagenesis","volume":"275","author":"EE Scott","year":"2000","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0284834.ref071","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/nrm3949","article-title":"The selection and function of cell type-specific enhancers","volume":"16","author":"S Heinz","year":"2015","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"5","key":"pone.0284834.ref072","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.devcel.2021.02.016","article-title":"Enhancer grammar in development, evolution, and disease: dependencies and interplay","volume":"56","author":"GA Jindal","year":"2021","journal-title":"Dev Cell"},{"issue":"6","key":"pone.0284834.ref073","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/nrg1348","article-title":"Microsatellites: simple sequences with complex evolution","volume":"5","author":"H. Ellegren","year":"2004","journal-title":"Nat Rev Genet"},{"issue":"3","key":"pone.0284834.ref074","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/j.1365-294X.1993.tb00102.x","article-title":"Detection of highly polymorphic microsatellite loci in a species with little allozyme polymorphism","volume":"2","author":"CR Hughes","year":"1993","journal-title":"Mol Ecol"},{"issue":"12","key":"pone.0284834.ref075","doi-asserted-by":"crossref","first-page":"2123","DOI":"10.1093\/molbev\/msg228","article-title":"The relationship between microsatellite slippage mutation rate and the number of repeat units","volume":"20","author":"Y Lai","year":"2003","journal-title":"Mol Biol Evol"},{"key":"pone.0284834.ref076","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12935-019-1091-8","article-title":"Microsatellite instability: a review of what the oncologist should know","volume":"20","author":"K Li","year":"2020","journal-title":"Cancer Cell Int"},{"issue":"10","key":"pone.0284834.ref077","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1101\/gad.4.10.1811","article-title":"Muscle-specific expression of the cardiac alpha-actin gene requires MyoD1, CArG-box binding factor, and Sp1","volume":"4","author":"V Sartorelli","year":"1990","journal-title":"Genes Dev"},{"issue":"11","key":"pone.0284834.ref078","doi-asserted-by":"crossref","first-page":"5991","DOI":"10.1128\/MCB.15.11.5991","article-title":"Transcription of the human beta enolase gene (ENO-3) is regulated by an intronic muscle-specific enhancer that binds myocyte-specific enhancer factor 2 proteins and ubiquitous G-rich-box binding factors.","volume":"15","author":"S Feo","year":"1995","journal-title":"Mol Cell Biol"},{"issue":"2","key":"pone.0284834.ref079","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.trechm.2019.07.002","article-title":"The Structure and Function of DNA G-Quadruplexes.","volume":"2","author":"J Spiegel","year":"2020","journal-title":"Trends Chem."},{"issue":"12","key":"pone.0284834.ref080","doi-asserted-by":"crossref","first-page":"3916","DOI":"10.1093\/nar\/gkn340","article-title":"Differential binding of quadruplex structures of muscle-specific genes regulatory sequences by MyoD, MRF4 and myogenin","volume":"36","author":"A Yafe","year":"2008","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pone.0284834.ref081","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12915-021-00980-y","article-title":"Loss of splicing factor IK impairs normal skeletal muscle development","volume":"19","author":"HI Ka","year":"2021","journal-title":"BMC Biol"},{"issue":"D1","key":"pone.0284834.ref082","doi-asserted-by":"crossref","first-page":"D480","DOI":"10.1093\/nar\/gkaa1100","article-title":"UniProt: the universal protein knowledgebase in 2021.","volume":"49","author":"UniProt Consortium","year":"2021","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pone.0284834.ref083","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.3390\/ijms21031153","article-title":"Understanding the Role of the Transcription Factor Sp1 in Ovarian Cancer: from Theory to Practice.","volume":"21","author":"B Vellingiri","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"10","key":"pone.0284834.ref084","first-page":"4854","article-title":"Myogenin induces the myocyte-specific enhancer binding factor MEF-2 independently of other muscle-specific gene products","volume":"11","author":"P Cserjesi","year":"1991","journal-title":"Mol Cell Biol"},{"issue":"2","key":"pone.0284834.ref085","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1128\/MCB.01415-06","article-title":"Regulation of HDAC9 gene expression by MEF2 establishes a negative-feedback loop in the transcriptional circuitry of muscle differentiation","volume":"27","author":"M Haberland","journal-title":"Mol Cell Biol"},{"issue":"4","key":"pone.0284834.ref086","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.yexcr.2012.12.016","article-title":"Regulation of MEF2 transcriptional activity by calcineurin\/mAKAP complexes","volume":"319","author":"J Li","year":"2013","journal-title":"Exp Cell Res"},{"issue":"45","key":"pone.0284834.ref087","doi-asserted-by":"crossref","first-page":"28514","DOI":"10.1016\/S0021-9258(18)46957-8","article-title":"Myocyte enhancer factor 2 (MEF2) binding site is essential for C2C12 myotube-specific expression of the rat GLUT4\/muscle-adipose facilitative glucose transporter gene.","volume":"269","author":"ML Liu","year":"1994","journal-title":"J Biol Chem"},{"issue":"9","key":"pone.0284834.ref088","doi-asserted-by":"crossref","first-page":"3575","DOI":"10.1128\/MCB.25.9.3575-3582.2005","article-title":"Myocyte enhancer factor 2 acetylation by p300 enhances its DNA binding activity, transcriptional activity, and myogenic differentiation","volume":"25","author":"K Ma","year":"2005","journal-title":"Mol Cell Biol"},{"issue":"2","key":"pone.0284834.ref089","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1093\/nar\/21.2.335","article-title":"Regulation of the mouse desmin gene: transactivated by MyoD, myogenin, MRF4 and Myf5","volume":"21","author":"H Li","year":"1993","journal-title":"Nucleic Acids Res"},{"issue":"4984","key":"pone.0284834.ref090","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1126\/science.2174572","article-title":"Differences and similarities in DNA-binding preferences of MyoD and E2A protein complexes revealed by binding site selection","volume":"250","author":"TK Blackwell","year":"1990","journal-title":"Science"},{"issue":"22","key":"pone.0284834.ref091","doi-asserted-by":"crossref","first-page":"4623","DOI":"10.1242\/dev.128.22.4623","article-title":"The Mef2c gene is a direct transcriptional target of myogenic bHLH and MEF2 proteins during skeletal muscle development","volume":"128","author":"DZ Wang","year":"2001","journal-title":"Development"},{"issue":"7","key":"pone.0284834.ref092","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/0092-8674(95)90139-6","article-title":"Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins","volume":"83","author":"JD Molkentin","year":"1995","journal-title":"Cell"},{"key":"pone.0284834.ref093","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1146\/annurev.cellbio.14.1.167","article-title":"Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins.","volume":"14","author":"BL Black","year":"1998","journal-title":"Annu Rev Cell Dev Biol"},{"issue":"15","key":"pone.0284834.ref094","doi-asserted-by":"crossref","first-page":"5623","DOI":"10.1073\/pnas.87.15.5623","article-title":"MyoD binds cooperatively to two sites in a target enhancer sequence: occupancy of two sites is required for activation","volume":"87","author":"H Weintraub","year":"1990","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pone.0284834.ref095","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1128\/MCB.19.4.2577","article-title":"Myogenic basic helix-loop-helix proteins and Sp1 interact as components of a multiprotein transcriptional complex required for activity of the human cardiac alpha-actin promoter","volume":"19","author":"E Biesiada","year":"1999","journal-title":"Mol Cell Biol"},{"issue":"12","key":"pone.0284834.ref096","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1242\/dev.01874","article-title":"The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription","volume":"132","author":"SJ Tapscott","year":"2005","journal-title":"Development"},{"issue":"4","key":"pone.0284834.ref097","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1002\/jcb.10397","article-title":"Chromatin remodeling as a guide to transcriptional regulatory networks in mammals","volume":"88","author":"FD Urnov","year":"2003","journal-title":"J Cell Biochem"},{"issue":"1","key":"pone.0284834.ref098","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s13059-021-02322-1","article-title":"Mechanisms of enhancer action: the known and the unknown","volume":"22","year":"2021","journal-title":"Genome Biol"},{"issue":"3","key":"pone.0284834.ref099","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/S1471-4892(03)00050-X","article-title":"Role of transcription factors in skeletal muscle and the potential for pharmacological manipulation","volume":"3","author":"PT Martin","year":"2003","journal-title":"Curr Opin Pharmacol"},{"issue":"2","key":"pone.0284834.ref100","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/0042-6822(73)90341-3","article-title":"A new technique for the assay of infectivity of human adenovirus 5 DNA.","volume":"52","author":"FL Graham","year":"1973","journal-title":"Virology"},{"key":"pone.0284834.ref101","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1146\/annurev.immunol.15.1.707","article-title":"Transcription factors of the NFAT family: regulation and function","volume":"15","author":"A Rao","year":"1997","journal-title":"Annu Rev Immunol"},{"issue":"29","key":"pone.0284834.ref102","doi-asserted-by":"crossref","first-page":"10590","DOI":"10.1073\/pnas.0308035101","article-title":"NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching","volume":"101","author":"KJ McCullagh","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"pone.0284834.ref103","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0165-6147(02)02111-9","article-title":"Calcineurin signaling and neural control of skeletal muscle fiber type and size","volume":"23","author":"S Schiaffino","year":"2002","journal-title":"Trends Pharmacol Sci"},{"key":"pone.0284834.ref104","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.marenvres.2017.06.018","article-title":"Marine mammal cell cultures: To obtain, to apply, and to preserve","volume":"129","author":"AV Boroda","year":"2017","journal-title":"Mar Environ Res"},{"issue":"2","key":"pone.0284834.ref105","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/35052548","article-title":"Genomic strategies to identify mammalian regulatory sequences","volume":"2","author":"LA Pennacchio","year":"2001","journal-title":"Nat Rev Genet"},{"issue":"3","key":"pone.0284834.ref106","doi-asserted-by":"crossref","first-page":"e1002929","DOI":"10.1371\/journal.pcbi.1002929","article-title":"Positively selected sites in cetacean myoglobins contribute to protein stability.","volume":"9","author":"P Dasmeh","year":"2013","journal-title":"PLoS Comput Biol."},{"issue":"3","key":"pone.0284834.ref107","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1152\/japplphysiol.00973.2013","article-title":"Changing the paradigm for myoglobin: a novel link between lipids and myoglobin","volume":"117","author":"AE Schlater","year":"2014","journal-title":"J Appl Physiol (1985)."},{"issue":"4","key":"pone.0284834.ref108","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/0092-8674(83)90300-8","article-title":"Cytoplasmic activation of human nuclear genes in stable heterocaryons","volume":"32","author":"HM Blau","year":"1983","journal-title":"Cell"},{"key":"pone.0284834.ref109","first-page":"2010","volume-title":"Intuitive Biostatistics, 3rd edition.","author":"HJ Motulsky","year":"2010"},{"issue":"13","key":"pone.0284834.ref110","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.1093\/nar\/gkg585","article-title":"MATCH: A tool for searching transcription factor binding sites in DNA sequences","volume":"31","author":"AE Kel","year":"2003","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pone.0284834.ref111","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2144\/000113999","article-title":"LASAGNA-Search: an integrated web tool for transcription factor binding site search and visualization","volume":"54","author":"C Lee","year":"2013","journal-title":"Biotechniques"},{"issue":"Web Server issue","key":"pone.0284834.ref112","doi-asserted-by":"crossref","first-page":"W217","DOI":"10.1093\/nar\/gkh383","article-title":"rVISTA 2.0: evolutionary analysis of transcription factor binding sites","volume":"32","author":"GG Loots","year":"2004","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pone.0284834.ref113","doi-asserted-by":"crossref","first-page":"D165","DOI":"10.1093\/nar\/gkab1113","article-title":"JASPAR 2022: the 9th release of the open-access database of transcription factor binding profiles.","volume":"50","author":"JA Castro-Mondragon","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"pone.0284834.ref114","doi-asserted-by":"crossref","first-page":"1.30.1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses.","volume":"54","author":"G Stelzer","year":"2016","journal-title":"Curr Protoc Bioinformatics"},{"issue":"6220","key":"pone.0284834.ref115","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome.","volume":"347","author":"M Uhl\u00e9n","year":"2015","journal-title":"Science"},{"issue":"4","key":"pone.0284834.ref116","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1101\/gr.10.4.577","article-title":"PipMaker\u2014a web server for aligning two genomic DNA sequences","volume":"10","author":"S Schwartz","year":"2000","journal-title":"Genome Res"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0284834","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T17:54:01Z","timestamp":1693331641000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0284834"}},"subtitle":[],"editor":[{"given":"Julie","family":"Dumonceaux","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,8,29]]},"references-count":116,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0284834","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2023,8,29]]}}}