Capturing Hidden Regulation based on Noise Change of Gene Expression Level from Single Cell RNA-seq in Yeast

Capturing Hidden Regulation based on Noise Change of Gene Expression Level from Single Cell RNA-seq in Yeast | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Capturing Hidden Regulation based on Noise Change of Gene Expression Level from Single Cell RNA-seq in Yeast Thoma Itoh, Takashi Makino This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-669168/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Nov, 2021 Read the published version in Scientific Reports → Version 1 posted 9 You are reading this latest preprint version Abstract Recent progress in high throughput single cell RNA-seq (scRNA-seq) has activated the development of data-driven inferring methods of gene regulatory networks. Most network estimations assume that perturbations produce downstream effects. However, the effects of gene perturbations are sometimes compensated by a gene with redundant functionality (functional compensation). In order to avoid functional compensation, previous studies constructed double gene deletions, but its vast nature of gene combinations was not suitable for comprehensive network estimation. We hypothesized that functional compensation may emerge as a noise change without mean change (noise-only change) due to varying physical properties and strong compensation effects. Here, we show compensated interactions, which are not detected by mean change, are captured by noise-only change quantified from scRNA-seq. We investigated whether noise-only change genes caused by a single deletion of STP1 and STP2, which have strong functional compensation, are enriched in redundantly regulated genes. As a result, noise-only change genes are enriched in their redundantly regulated genes. Furthermore, novel downstream genes detected from noise change are enriched in “transport”, which is related to known downstream genes. Herein, we suggest the noise difference comparison has the potential to be applied as a new strategy for network estimation that capture even compensated interaction. Scientific Communication General Cell Biology & Physiology Gene regulatory network expression noise Figures Figure 1 Figure 2 Figure 3 Figure 4 Full Text Table Due to technical limitations, table 1 is only available as a download in the Supplemental Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.pdf Supplementary.pdf Cite Share Download PDF Status: Published Journal Publication published 19 Nov, 2021 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Major revision 26 Aug, 2021 Reviews received at journal 19 Aug, 2021 Reviewers agreed at journal 30 Jul, 2021 Reviewers agreed at journal 26 Jul, 2021 Reviewers invited by journal 26 Jul, 2021 Editor assigned by journal 26 Jul, 2021 Editor invited by journal 05 Jul, 2021 Submission checks completed at journal 05 Jul, 2021 First submitted to journal 29 Jun, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-669168","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":37343491,"identity":"ac51493a-00ef-46dc-bf54-d62e01619263","order_by":0,"name":"Thoma Itoh","email":"","orcid":"","institution":"Department of Biology, Faculty of Science, Tohoku University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Thoma","middleName":"","lastName":"Itoh","suffix":""},{"id":37343496,"identity":"0d8f1440-ebd9-42c6-bcba-5d903cfc35c9","order_by":1,"name":"Takashi Makino","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYJACxgYDBgZ+BgY2BoYDEBEDfMp5YFok20jTAlJ1DEkLXmDPfjrx44yCO3LG95uPPfhw5jADf/sBhuICfLbw5G6W3GDwzNjsGFu64YwbhxkkziQwGM/A67DcDZIPDA4nbjvGYybN8+EwA8MNBgZjHnxa+N9u/gnSsrkNqkWeoBaJ3G1Ahx1O3MAG0gJ0mAFBLTfebrOcYXDYWOJYWprkjDPpPIZnEhvw+oW9P3fzzZ4/h+X4mw8fk/hwzFpO7vjhY8b4QgzTWmA8tRmTogMMmB+TrGUUjIJRMAqGMwAAHBNNheHYy/gAAAAASUVORK5CYII=","orcid":"","institution":"Graduate School of Life Sciences, Tohoku University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Makino","suffix":""}],"badges":[],"createdAt":"2021-06-30 00:59:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-669168/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-669168/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-021-01558-y","type":"published","date":"2021-11-19T12:20:46+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":11210054,"identity":"523d6d1e-4f38-42c7-9189-dab588248ab7","added_by":"auto","created_at":"2021-07-07 14:09:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82533,"visible":true,"origin":"","legend":"Noise difference detects functional compensation. STP1 and STP2\nredundant pathway (Right: Wildtype, Left: STP2 deletion mutant). The lack of STP2\nis compensated by STP1, resulting in no change in the mean expression level of\ndownstream genes (orange circles). However, expression noise that propagated from\nupstream changes differ due to changes in physical characteristics of upstream genes.","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-669168/v1/7d4bf0ebd2f4d02f7de7eb5f.png"},{"id":11210051,"identity":"0883afa9-64d7-4aee-a182-47a620946267","added_by":"auto","created_at":"2021-07-07 14:09:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":280133,"visible":true,"origin":"","legend":"Enrichment test of mean change genes to known downstream genes\nshared by homologous groups.\nThe bar graph shows whether the mean change genes in each deletion strain are\nenriched in the common downstream genes of the groups in which the deleted gene\nbelongs. (a) Redundant gene group; STP1 and STP2. (b) Non redundant gene group;\nRTG1 and RTG3. (c) Possibly redundant paralogous group; GATA family (DAL80,\nGAT1, GLN3, and GZF3). The p-value above the bar graphs were calculated using\nFisher’s exact test. The dark bars on the left show the proportion of known common\ninteractions (red) and unknown common interactions (blue) in the mean change genes\n(FDR \u003c 0.05). The light bars on the right show the proportion of known common\ninteractions (red) and unknown common interactions (blue) in the non-mean change\ngenes. The vertical axis represents the proportion, and the numbers on the bars show\nthe number of genes in each category. If the red area on left is significantly larger than\nthat on right, it indicates that mean change genes are enriched in common downstream\ngenes.","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-669168/v1/2409217022c0d1eec08eea4c.png"},{"id":11209615,"identity":"2066c7a1-0f89-4440-88fd-e08a44ac2dd2","added_by":"auto","created_at":"2021-07-07 14:06:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":318811,"visible":true,"origin":"","legend":"Enrichment test of noise-only change genesto known downstream genes\nshared by homologous groups.\nThe bar graph shows whether the noise-only change genes in each deletion strains are\nenriched in the common downstream genes of the groups in which the deleted gene\nbelongs. (a) Redundant gene group; STP1 and STP2. (b) Non redundant gene group;\nRTG1 and RTG3. (c) Possibly redundant paralogous group; GATA family (DAL80,\nGAT1, GLN3, and GZF3). The p-value above the bar graphs were calculated using\nFisher’s exact test. The dark bars on the left indicate the proportion of known commoninteractions (red) and unknown common interactions (blue) in the noise-only change\ngenes (FDR \u003c 0.05). The light bars on the right indicate the proportion of known\ncommon interactions (red) and unknown common interactions (blue) in the non-noise\u0002only change genes. The vertical axis represents the proportion, and the numbers on the\nbars show the number of genes in each category. If the red area on left is significantly\nlarger than that on right, it indicates that noise-only change genes are enriched in\ncommon downstream genes.","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-669168/v1/e0e11bb2fdd9cd82174d990e.png"},{"id":11210163,"identity":"cd6ead0f-e421-4a79-a2b8-005b2f76ba7d","added_by":"auto","created_at":"2021-07-07 14:12:42","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":290691,"visible":true,"origin":"","legend":"Gene regulatory network shared by STP1 and STP2. Dark arrows\nsuggest the interaction detected from noise-only change. Red and blue arrows imply\nknown and novel interactions, respectively. Light red arrows suggest known\ninteractions that cannot be detected from noise-only changes in this study. Wide red\narrows imply that the interaction was previously detected from a single deletion, and\nthe thin red arrows imply the interaction was previously detected from a double\ndeletion. Dashed lines indicate a synthetic effect, which are negative synthetic\ninteraction (NS) or positive synthetic interaction (PS). The color of gene names implies\nGO terms retrieved from SGD GO Slim mapper. SIT1 and FIT3 depicts profile\nsimilarity defined by the similarity of synthetic interactions.","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-669168/v1/8a641ce4aec8230cd4171ccd.jpg"},{"id":15708676,"identity":"cebbf13f-6135-414c-9537-70722502e84f","added_by":"auto","created_at":"2021-11-19 12:20:59","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":644970,"visible":true,"origin":"","legend":"","description":"","filename":"Paper2V15.pdf","url":"https://assets-eu.researchsquare.com/files/rs-669168/v1_covered.pdf"},{"id":13655987,"identity":"96b97988-b3d0-4829-b455-5abbc2059380","added_by":"auto","created_at":"2021-09-17 10:04:27","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":639856,"visible":true,"origin":"","legend":"","description":"","filename":"Paper2V15.pdf","url":"https://assets-eu.researchsquare.com/files/rs-669168/v1_covered.pdf"},{"id":11210164,"identity":"ae55abe8-899c-4572-a8ec-6a44b92e7b56","added_by":"auto","created_at":"2021-07-07 14:12:49","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":636156,"visible":true,"origin":"","legend":"","description":"","filename":"Paper2V15.pdf","url":"https://assets-eu.researchsquare.com/files/rs-669168/v1_covered.pdf"},{"id":11210052,"identity":"81090aa1-a14e-4ce8-be9a-026a5b0c485a","added_by":"auto","created_at":"2021-07-07 14:09:42","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33185,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-669168/v1/4d0695b6e6e1e4de9cca15cf.pdf"},{"id":11210055,"identity":"2fb70a98-ae40-4be2-9fbf-53214d0def86","added_by":"auto","created_at":"2021-07-07 14:09:42","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3789781,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.pdf","url":"https://assets-eu.researchsquare.com/files/rs-669168/v1/09e418f7f75f781bef38db5c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eCapturing Hidden Regulation based on Noise Change of Gene Expression Level from Single Cell RNA-seq in Yeast\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"This preprint is available for \u003ca href='/article/rs-669168/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e."},{"header":"Table","content":"\u003cp\u003eDue to technical limitations, table 1 is only available as a download in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gene regulatory network, expression noise","lastPublishedDoi":"10.21203/rs.3.rs-669168/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-669168/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Recent progress in high throughput single cell RNA-seq (scRNA-seq) has activated the development of data-driven inferring methods of gene regulatory networks. Most network estimations assume that perturbations produce downstream effects. However, the effects of gene perturbations are sometimes compensated by a gene with redundant functionality (functional compensation). In order to avoid functional compensation, previous studies constructed double gene deletions, but its vast nature of gene combinations was not suitable for comprehensive network estimation. We hypothesized that functional compensation may emerge as a noise change without mean change (noise-only change) due to varying physical properties and strong compensation effects. Here, we show compensated interactions, which are not detected by mean change, are captured by noise-only change quantified from scRNA-seq. We investigated whether noise-only change genes caused by a single deletion of STP1 and STP2, which have strong functional compensation, are enriched in redundantly regulated genes. As a result, noise-only change genes are enriched in their redundantly regulated genes. Furthermore, novel downstream genes detected from noise change are enriched in “transport”, which is related to known downstream genes. Herein, we suggest the noise difference comparison has the potential to be applied as a new strategy for network estimation that capture even compensated interaction.","manuscriptTitle":"Capturing Hidden Regulation based on Noise Change of Gene Expression Level from Single Cell RNA-seq in Yeast","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-07-07 14:06:40","doi":"10.21203/rs.3.rs-669168/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-08-26T05:34:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-08-19T21:54:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"76671020-c53e-4c5c-af44-106811ad8104","date":"2021-07-30T21:38:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"701befb9-03cb-4d81-b067-338bfdef60f4","date":"2021-07-26T23:00:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-07-26T18:01:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2021-07-26T15:53:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2021-07-05T10:48:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2021-07-05T06:58:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2021-06-30T00:57:56+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"06084cdb-b33a-4fe2-8c37-f7806f39a45a","owner":[],"postedDate":"July 7th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":5506106,"name":"Scientific Communication"},{"id":5506107,"name":"General Cell Biology \u0026 Physiology"}],"tags":[],"updatedAt":"2021-11-19T12:20:46+00:00","versionOfRecord":{"articleIdentity":"rs-669168","link":"https://doi.org/10.1038/s41598-021-01558-y","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2021-11-19 12:20:46","publishedOnDateReadable":"November 19th, 2021"},"versionCreatedAt":"2021-07-07 14:06:40","video":"","vorDoi":"10.1038/s41598-021-01558-y","vorDoiUrl":"https://doi.org/10.1038/s41598-021-01558-y","workflowStages":[]},"version":"v1","identity":"rs-669168","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-669168","identity":"rs-669168","version":["v1"]},"buildId":"ApUGefWb6u5IBVtyqm6d5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}