{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T01:33:28Z","timestamp":1780709608106,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1011802","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T00:00:00Z","timestamp":1706227200000}}],"reference-count":100,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T00:00:00Z","timestamp":1705363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM121755"],"award-info":[{"award-number":["GM121755"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM092910"],"award-info":[{"award-number":["GM092910"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY030075"],"award-info":[{"award-number":["EY030075"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL149961"],"award-info":[{"award-number":["HL149961"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH122451"],"award-info":[{"award-number":["MH122451"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000051","name":"National Human Genome Research Institute","doi-asserted-by":"publisher","award":["HG011431"],"award-info":[{"award-number":["HG011431"]}],"id":[{"id":"10.13039\/100000051","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    The effects of transcription factor binding sites (TFBSs) on the activity of a\n                    <jats:italic>cis<\/jats:italic>\n                    -regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence context that determines whether CRX binding sites contribute to activation or repression of transcription is not understood. To investigate the context-dependent activity of CRX sites, we fit neural network-based models to the activities of synthetic CREs composed of photoreceptor TFBSs. The models revealed that CRX binding sites consistently make positive, independent contributions to CRE activity, while negative homotypic interactions between sites cause CREs composed of multiple CRX sites to function as silencers. The effects of negative homotypic interactions can be overcome by the presence of other TFBSs that either interact cooperatively with CRX sites or make independent positive contributions to activity. The context-dependent activity of CRX sites is thus determined by the balance between positive heterotypic interactions, independent contributions of TFBSs, and negative homotypic interactions. Our findings explain observed patterns of activity among genomic CRX-bound enhancers and silencers, and suggest that enhancers may require diverse TFBSs to overcome negative homotypic interactions between TFBSs.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1011802","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T13:29:43Z","timestamp":1705411783000},"page":"e1011802","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Transcription factor interactions explain the context-dependent activity of CRX binding sites"],"prefix":"10.1371","volume":"20","author":[{"given":"Kaiser J.","family":"Loell","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9013-8676","authenticated-orcid":true,"given":"Ryan Z.","family":"Friedman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie A.","family":"Myers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph C.","family":"Corbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barak A.","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8511-6026","authenticated-orcid":true,"given":"Michael A.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"pcbi.1011802.ref001","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/s41586-020-2023-4","article-title":"Occupancy maps of 208 chromatin-associated proteins in one human cell type","volume":"583","author":"EC Partridge","year":"2020","journal-title":"Nature"},{"key":"pcbi.1011802.ref002","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/s41586-020-2528-x","article-title":"Global reference mapping of human transcription factor footprints","volume":"583","author":"J Vierstra","year":"2020","journal-title":"Nature"},{"key":"pcbi.1011802.ref003","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1038\/s41586-020-2493-4","article-title":"Expanded encyclopaedias of DNA elements in the human and mouse genomes","volume":"583","author":"Moore JE ENCODE Project Consortium","year":"2020","journal-title":"Nature"},{"key":"pcbi.1011802.ref004","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.1002\/j.1460-2075.1993.tb05989.x","article-title":"Conversion of a dorsal-dependent silencer into an enhancer: evidence for dorsal corepressors","volume":"12","author":"J Jiang","year":"1993","journal-title":"EMBO J"},{"key":"pcbi.1011802.ref005","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1242\/dev.00286","article-title":"Requirements for transcriptional repression and activation by Engrailed in Drosophila embryos","volume":"130","author":"C Alexandre","year":"2003","journal-title":"Development"},{"key":"pcbi.1011802.ref006","doi-asserted-by":"crossref","first-page":"8811","DOI":"10.1073\/pnas.1432147100","article-title":"GATA-1-dependent transcriptional repression of GATA-2 via disruption of positive autoregulation and domain-wide chromatin remodeling","volume":"100","author":"JA Grass","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011802.ref007","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1210\/me.2004-0006","article-title":"The transcriptional repressor Nkx6.1 also functions as a deoxyribonucleic acid context-dependent transcriptional activator during pancreatic beta-cell differentiation: evidence for feedback activation of the nkx6.1 gene by Nkx6.1","volume":"18","author":"T Iype","year":"2004","journal-title":"Mol Endocrinol"},{"key":"pcbi.1011802.ref008","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/hmg\/ddi070","article-title":"The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes","volume":"14","author":"G-H Peng","year":"2005","journal-title":"Hum Mol Genet"},{"key":"pcbi.1011802.ref009","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1128\/EC.00037-13","article-title":"Activator and repressor functions of the Mot3 transcription factor in the osmostress response of Saccharomyces cerevisiae","volume":"12","author":"F Mart\u00ednez-Monta\u00f1\u00e9s","year":"2013","journal-title":"Eukaryot Cell"},{"key":"pcbi.1011802.ref010","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1126\/science.aab3417","article-title":"Single-base pair differences in a shared motif determine differential Rhodopsin expression","volume":"350","author":"J Rister","year":"2015","journal-title":"Science"},{"key":"pcbi.1011802.ref011","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/nature15545","article-title":"Transcriptional regulators form diverse groups with context-dependent regulatory functions","volume":"528","author":"G Stampfel","year":"2015","journal-title":"Nature"},{"key":"pcbi.1011802.ref012","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.ijcard.2015.05.108","article-title":"FHL2 switches MITF from activator to repressor of Erbin expression during cardiac hypertrophy.","volume":"195","author":"I Rachmin","year":"2015","journal-title":"Int J Cardiol"},{"key":"pcbi.1011802.ref013","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1016\/j.celrep.2016.09.066","article-title":"A Simple Grammar Defines Activating and Repressing cis-Regulatory Elements","volume":"17","author":"MA White","year":"2016","journal-title":"Photoreceptors. Cell Rep"},{"key":"pcbi.1011802.ref014","doi-asserted-by":"crossref","first-page":"E1291","DOI":"10.1073\/pnas.1621150114","article-title":"Systematic dissection of genomic features determining transcription factor binding and enhancer function","volume":"114","author":"SR Grossman","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011802.ref015","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.cels.2017.08.011","article-title":"Multiplex Enhancer Interference Reveals Collaborative Control of Gene Regulation by Estrogen Receptor \u03b1-Bound Enhancers","volume":"5","author":"JB Carleton","year":"2017","journal-title":"Cell Syst"},{"key":"pcbi.1011802.ref016","first-page":"9","article-title":"Synthetic and genomic regulatory elements reveal aspects of cis-regulatory grammar in mouse embryonic stem cells","author":"DM King","year":"2020","journal-title":"Elife"},{"key":"pcbi.1011802.ref017","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.molcel.2020.12.040","article-title":"The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages","volume":"81","author":"Z Huang","year":"2021","journal-title":"Mol Cell"},{"key":"pcbi.1011802.ref018","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.67403","article-title":"Information content differentiates enhancers from silencers in mouse photoreceptors.","volume":"10","author":"RZ Friedman","year":"2021","journal-title":"Elife."},{"key":"pcbi.1011802.ref019","doi-asserted-by":"crossref","first-page":"4246","DOI":"10.1016\/j.cub.2021.07.030","article-title":"Cell-type-specific Hox regulatory strategies orchestrate tissue identity","volume":"31","author":"R Loker","year":"2021","journal-title":"Curr Biol"},{"key":"pcbi.1011802.ref020","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ydbio.2021.03.010","article-title":"Cis-regulatory code for determining the action of Foxd as both an activator and a repressor in ascidian embryos","volume":"476","author":"S Tokuhiro","year":"2021","journal-title":"Dev Biol"},{"key":"pcbi.1011802.ref021","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"},{"key":"pcbi.1011802.ref022","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.cell.2016.09.018","article-title":"Ever-Changing Landscapes: Transcriptional Enhancers in Development and Evolution","volume":"167","author":"HK Long","year":"2016","journal-title":"Cell"},{"key":"pcbi.1011802.ref023","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/nrg3207","article-title":"Transcription factors: from enhancer binding to developmental control","volume":"13","author":"F Spitz","year":"2012","journal-title":"Nat Rev Genet"},{"key":"pcbi.1011802.ref024","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/jcb.20352","article-title":"Transcriptional enhancers: Intelligent enhanceosomes or flexible billboards?","volume":"94","author":"DN Arnosti","year":"2005","journal-title":"J Cell Biochem"},{"key":"pcbi.1011802.ref025","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/0092-8674(95)90136-1","article-title":"Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome","volume":"83","author":"D Thanos","year":"1995","journal-title":"Cell"},{"key":"pcbi.1011802.ref026","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.cell.2012.01.030","article-title":"A transcription factor collective defines cardiac cell fate and reflects lineage history","volume":"148","author":"G Junion","year":"2012","journal-title":"Cell"},{"key":"pcbi.1011802.ref027","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1101\/gad.976502","article-title":"Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling","volume":"16","author":"S Barolo","year":"2002","journal-title":"Genes Dev"},{"key":"pcbi.1011802.ref028","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41588-020-0578-5","article-title":"Systematic identification of silencers in human cells","volume":"52","author":"B Pang","year":"2020","journal-title":"Nat Genet"},{"key":"pcbi.1011802.ref029","article-title":"Identification of non-coding silencer elements and their regulation of gene expression","author":"B Pang","year":"2022","journal-title":"Nat Rev Mol Cell Biol"},{"key":"pcbi.1011802.ref030","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.tig.2021.02.002","article-title":"Transcriptional Silencers: Driving Gene Expression with the Brakes On","volume":"37","author":"JA Segert","year":"2021","journal-title":"Trends Genet"},{"key":"pcbi.1011802.ref031","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1101\/gr.109405.110","article-title":"CRX ChIP-seq reveals the cis-regulatory architecture of mouse photoreceptors","volume":"20","author":"JC Corbo","year":"2010","journal-title":"Genome Res"},{"key":"pcbi.1011802.ref032","doi-asserted-by":"crossref","first-page":"43184","DOI":"10.1038\/srep43184","article-title":"Cell Type-Specific Epigenomic Analysis Reveals a Uniquely Closed Chromatin Architecture in Mouse Rod Photoreceptors.","volume":"7","author":"AEO Hughes","year":"2017","journal-title":"Sci Rep"},{"key":"pcbi.1011802.ref033","first-page":"8","article-title":"Cis-regulatory basis of sister cell type divergence in the vertebrate retina","author":"DP Murphy","year":"2019","journal-title":"Elife"},{"key":"pcbi.1011802.ref034","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0092-8674(00)80439-0","article-title":"Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation","volume":"91","author":"T Furukawa","year":"1997","journal-title":"Cell"},{"key":"pcbi.1011802.ref035","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/S0896-6273(00)80394-3","article-title":"Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes","volume":"19","author":"S Chen","year":"1997","journal-title":"Neuron"},{"key":"pcbi.1011802.ref036","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/S0092-8674(00)80440-7","article-title":"Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor.","volume":"91","author":"CL Freund","year":"1997","journal-title":"Cell"},{"key":"pcbi.1011802.ref037","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1093\/hmg\/ddh173","article-title":"Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors","volume":"13","author":"H Cheng","year":"2004","journal-title":"Hum Mol Genet"},{"key":"pcbi.1011802.ref038","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1210\/me.2005-0505","article-title":"Activation of the blue opsin gene in cone photoreceptor development by retinoid-related orphan receptor beta","volume":"20","author":"M Srinivas","year":"2006","journal-title":"Mol Endocrinol"},{"key":"pcbi.1011802.ref039","doi-asserted-by":"crossref","first-page":"e643","DOI":"10.1371\/journal.pone.0000643","article-title":"The cis-regulatory logic of the mammalian photoreceptor transcriptional network.","volume":"2","author":"TH-C Hsiau","year":"2007","journal-title":"PLoS One."},{"key":"pcbi.1011802.ref040","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.brainres.2007.06.036","article-title":"Regulation of photoreceptor gene expression by Crx-associated transcription factor network","volume":"1192","author":"AK Hennig","year":"2008","journal-title":"Brain Res"},{"key":"pcbi.1011802.ref041","doi-asserted-by":"crossref","first-page":"36921","DOI":"10.1074\/jbc.M111.279026","article-title":"Transcriptional regulation of neural retina leucine zipper (Nrl), a photoreceptor cell fate determinant.","volume":"286","author":"CL Montana","year":"2011","journal-title":"J Biol Chem"},{"key":"pcbi.1011802.ref042","doi-asserted-by":"crossref","first-page":"9001","DOI":"10.1073\/pnas.1922501117","article-title":"Mapping the cis-regulatory architecture of the human retina reveals noncoding genetic variation in disease","volume":"117","author":"TJ Cherry","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011802.ref043","doi-asserted-by":"crossref","first-page":"11952","DOI":"10.1073\/pnas.1307449110","article-title":"Massively parallel in vivo enhancer assay reveals that highly local features determine the cis-regulatory function of ChIP-seq peaks","volume":"110","author":"MA White","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011802.ref044","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1101\/gr.231886.117","article-title":"A massively parallel reporter assay reveals context-dependent activity of homeodomain binding sites in vivo","volume":"28","author":"AEO Hughes","year":"2018","journal-title":"Genome Res"},{"key":"pcbi.1011802.ref045","doi-asserted-by":"crossref","first-page":"29794","DOI":"10.1074\/jbc.M003658200","article-title":"The leucine zipper of NRL interacts with the CRX homeodomain. A possible mechanism of transcriptional synergy in rhodopsin regulation","volume":"275","author":"KP Mitton","year":"2000","journal-title":"J Biol Chem"},{"key":"pcbi.1011802.ref046","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1017\/S0952523805225063","article-title":"Chromatin immunoprecipitation identifies photoreceptor transcription factor targets in mouse models of retinal degeneration: new findings and challenges","volume":"22","author":"G-H Peng","year":"2005","journal-title":"Vis Neurosci"},{"key":"pcbi.1011802.ref047","doi-asserted-by":"crossref","first-page":"e1002649","DOI":"10.1371\/journal.pgen.1002649","article-title":"Transcriptional regulation of rod photoreceptor homeostasis revealed by in vivo NRL targetome analysis","volume":"8","author":"H Hao","year":"2012","journal-title":"PLoS Genet"},{"key":"pcbi.1011802.ref048","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nature07521","article-title":"Analysis of combinatorial cis-regulation in synthetic and genomic promoters","volume":"457","author":"J Gertz","year":"2009","journal-title":"Nature"},{"key":"pcbi.1011802.ref049","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1101\/gr.157891.113","article-title":"Massively parallel synthetic promoter assays reveal the in vivo effects of binding site variants","volume":"23","author":"I Mogno","year":"2013","journal-title":"Genome Res"},{"key":"pcbi.1011802.ref050","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1093\/nar\/gkt1230","article-title":"Discrimination between thermodynamic models of cis-regulation using transcription factor occupancy data","volume":"42","author":"RD Zeigler","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1011802.ref051","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1101\/gr.200733.115","article-title":"Interactions between pluripotency factors specify cis-regulation in embryonic stem cells","volume":"26","author":"C Fiore","year":"2016","journal-title":"Genome Res"},{"key":"pcbi.1011802.ref052","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.gde.2005.02.007","article-title":"Transcriptional regulation by the numbers: models","volume":"15","author":"L Bintu","year":"2005","journal-title":"Curr Opin Genet Dev"},{"key":"pcbi.1011802.ref053","doi-asserted-by":"crossref","first-page":"9158","DOI":"10.1073\/pnas.1004290107","article-title":"Using deep sequencing to characterize the biophysical mechanism of a transcriptional regulatory sequence","volume":"107","author":"JB Kinney","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011802.ref054","doi-asserted-by":"crossref","first-page":"e1002407","DOI":"10.1371\/journal.pcbi.1002407","article-title":"Thermodynamic state ensemble models of cis-regulation.","volume":"8","author":"MS Sherman","year":"2012","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1011802.ref055","doi-asserted-by":"crossref","first-page":"E4796","DOI":"10.1073\/pnas.1722055115","article-title":"Systematic approach for dissecting the molecular mechanisms of transcriptional regulation in bacteria","volume":"115","author":"NM Belliveau","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011802.ref056","doi-asserted-by":"crossref","first-page":"e1006226","DOI":"10.1371\/journal.pcbi.1006226","article-title":"Mapping DNA sequence to transcription factor binding energy in vivo","volume":"15","author":"SL Barnes","year":"2019","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1011802.ref057","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13059-022-02661-7","article-title":"MAVE-NN: learning genotype-phenotype maps from multiplex assays of variant effect","volume":"23","author":"A Tareen","year":"2022","journal-title":"Genome Biol"},{"key":"pcbi.1011802.ref058","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41588-022-01048-5","article-title":"DeepSTARR predicts enhancer activity from DNA sequence and enables the de novo design of synthetic enhancers","volume":"54","author":"BP de Almeida","year":"2022","journal-title":"Nat Genet"},{"key":"pcbi.1011802.ref059","doi-asserted-by":"crossref","first-page":"e0218073","DOI":"10.1371\/journal.pone.0218073","article-title":"Deciphering regulatory DNA sequences and noncoding genetic variants using neural network models of massively parallel reporter assays","volume":"14","author":"R Movva","year":"2019","journal-title":"PLoS One"},{"key":"pcbi.1011802.ref060","article-title":"Enhancer grammar of liver cell types and hepatocyte zonation states","author":"CB Gonz\u00e1lez-Blas","year":"2022","journal-title":"bioRxiv"},{"key":"pcbi.1011802.ref061","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/s41588-021-01009-4","article-title":"Sequence determinants of human gene regulatory elements","volume":"54","author":"B Sahu","year":"2022","journal-title":"Nat Genet"},{"key":"pcbi.1011802.ref062","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1007\/s10955-015-1398-3","article-title":"Learning Quantitative Sequence\u2013Function Relationships from Massively Parallel Experiments","volume":"162","author":"GS Atwal","year":"2016","journal-title":"J Stat Phys"},{"key":"pcbi.1011802.ref063","doi-asserted-by":"crossref","first-page":"19498","DOI":"10.1073\/pnas.1210678109","article-title":"Complex effects of nucleotide variants in a mammalian cis-regulatory element","volume":"109","author":"JC Kwasnieski","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011802.ref064","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/ng774","article-title":"Nrl is required for rod photoreceptor development","volume":"29","author":"AJ Mears","year":"2001","journal-title":"Nat Genet"},{"key":"pcbi.1011802.ref065","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1242\/dev.126.1.23","article-title":"NeuroD regulates multiple functions in the developing neural retina in rodent","volume":"126","author":"EM Morrow","year":"1999","journal-title":"Development"},{"key":"pcbi.1011802.ref066","doi-asserted-by":"crossref","first-page":"17534","DOI":"10.1073\/pnas.0902425106","article-title":"Retinoid-related orphan nuclear receptor RORbeta is an early-acting factor in rod photoreceptor development","volume":"106","author":"L Jia","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011802.ref067","doi-asserted-by":"crossref","first-page":"20642","DOI":"10.1074\/jbc.M500957200","article-title":"Sp4 is expressed in retinal neurons, activates transcription of photoreceptor-specific genes, and synergizes with Crx","volume":"280","author":"LE Lerner","year":"2005","journal-title":"J Biol Chem"},{"key":"pcbi.1011802.ref068","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1038\/ng.2713","article-title":"Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model","volume":"45","author":"RP Smith","year":"2013","journal-title":"Nat Genet"},{"key":"pcbi.1011802.ref069","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S0092-8674(00)80592-9","article-title":"Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus","volume":"96","author":"N M\u00e9thot","year":"1999","journal-title":"Cell"},{"key":"pcbi.1011802.ref070","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2002077","article-title":"The cis-regulatory logic of Hedgehog gradient responses: key roles for gli binding affinity, competition, and cooperativity.","volume":"4","author":"DS Parker","year":"2011","journal-title":"Sci Signal."},{"key":"pcbi.1011802.ref071","article-title":"Nuclear microenvironments modulate transcription from low-affinity enhancers.","volume":"6","author":"A Tsai","year":"2017"},{"key":"pcbi.1011802.ref072","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1182\/blood.V99.7.2408","article-title":"The NFY transcription factor functions as a repressor and activator of the von Willebrand factor promoter","volume":"99","author":"Y Peng","year":"2002","journal-title":"Blood"},{"key":"pcbi.1011802.ref073","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1111\/j.1365-2958.2008.06389.x","article-title":"The Vibrio harveyi master quorum-sensing regulator, LuxR, a TetR-type protein is both an activator and a repressor: DNA recognition and binding specificity at target promoters","volume":"70","author":"AJ Pompeani","year":"2008","journal-title":"Mol Microbiol"},{"key":"pcbi.1011802.ref074","doi-asserted-by":"crossref","first-page":"5760","DOI":"10.1038\/onc.2015.352","article-title":"ZEB1 and TCF4 reciprocally modulate their transcriptional activities to regulate Wnt target gene expression","volume":"34","author":"E S\u00e1nchez-Till\u00f3","year":"2015","journal-title":"Oncogene"},{"key":"pcbi.1011802.ref075","doi-asserted-by":"crossref","first-page":"e89110","DOI":"10.1371\/journal.pone.0089110","article-title":"Otx2 ChIP-seq reveals unique and redundant functions in the mature mouse retina.","volume":"9","author":"A Samuel","year":"2014","journal-title":"PLoS One."},{"key":"pcbi.1011802.ref076","first-page":"147","article-title":"Differential abilities to engage inaccessible chromatin diversify vertebrate Hox binding patterns","author":"M Bulaji\u0107","year":"2020","journal-title":"Development"},{"key":"pcbi.1011802.ref077","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1101\/gr.272468.120","article-title":"A flexible repertoire of transcription factor binding sites and a diversity threshold determines enhancer activity in embryonic stem cells","volume":"31","author":"G Singh","year":"2021","journal-title":"Genome Res"},{"key":"pcbi.1011802.ref078","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1101\/gr.212316.116","article-title":"Large-scale mapping of gene regulatory logic reveals context-dependent repression by transcriptional activators","volume":"27","author":"D van Dijk","year":"2017","journal-title":"Genome Res"},{"key":"pcbi.1011802.ref079","doi-asserted-by":"crossref","first-page":"4021","DOI":"10.1074\/jbc.272.7.4021","article-title":"Sp3 is a bifunctional transcription regulator with modular independent activation and repression domains","volume":"272","author":"B Majello","year":"1997","journal-title":"J Biol Chem"},{"key":"pcbi.1011802.ref080","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/364454a0","article-title":"Dimerization and the control of transcription by Kr\u00fcppel","volume":"364","author":"F Sauer","year":"1993","journal-title":"Nature"},{"key":"pcbi.1011802.ref081","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1101\/gad.5.2.254","article-title":"Activation and repression of transcription by the gap proteins hunchback and Kr\u00fcppel in cultured Drosophila cells","volume":"5","author":"P Zuo","year":"1991","journal-title":"Genes Dev"},{"key":"pcbi.1011802.ref082","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abo6157","article-title":"Concentration-dependent transcriptional switching through a collective action of cis-elements.","volume":"8","author":"K Rodriguez","year":"2022","journal-title":"Sci Adv."},{"key":"pcbi.1011802.ref083","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1038\/s41467-020-16024-y","article-title":"Structural basis for the complex DNA binding behavior of the plant stem cell regulator WUSCHEL","volume":"11","author":"J Sloan","year":"2020","journal-title":"Nat Commun"},{"key":"pcbi.1011802.ref084","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/s41586-023-05906-y","article-title":"Large-scale mapping and mutagenesis of human transcriptional effector domains","volume":"616","author":"N DelRosso","year":"2023","journal-title":"Nature"},{"key":"pcbi.1011802.ref085","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1101\/gr.3394405","article-title":"Discovering functional transcription-factor combinations in the human cell cycle","volume":"15","author":"Z Zhu","year":"2005","journal-title":"Genome Res"},{"key":"pcbi.1011802.ref086","doi-asserted-by":"crossref","first-page":"e1115","DOI":"10.1371\/journal.pone.0001115","article-title":"Fine-tuning enhancer models to predict transcriptional targets across multiple genomes.","volume":"2","author":"S Aerts","year":"2007","journal-title":"PLoS One"},{"key":"pcbi.1011802.ref087","doi-asserted-by":"crossref","first-page":"R101","DOI":"10.1186\/gb-2007-8-6-r101","article-title":"Large-scale analysis of transcriptional cis-regulatory modules reveals both common features and distinct subclasses","volume":"8","author":"L Li","year":"2007","journal-title":"Genome Biol"},{"key":"pcbi.1011802.ref088","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1101\/gr.104471.109","article-title":"Homotypic clusters of transcription factor binding sites are a key component of human promoters and enhancers","volume":"20","author":"V Gotea","year":"2010","journal-title":"Genome Res"},{"key":"pcbi.1011802.ref089","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s12918-017-0485-2","article-title":"Synthetic enhancer design by in silico compensatory evolution reveals flexibility and constraint in cis-regulation","volume":"11","author":"KA Barr","year":"2017","journal-title":"BMC Syst Biol"},{"key":"pcbi.1011802.ref090","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/nbt.2205","article-title":"Inferring gene regulatory logic from high-throughput measurements of thousands of systematically designed promoters","volume":"30","author":"E Sharon","year":"2012","journal-title":"Nat Biotechnol"},{"key":"pcbi.1011802.ref091","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1038\/s41467-023-37960-5","article-title":"Transcription factor binding site orientation and order are major drivers of gene regulatory activity","volume":"14","author":"I Georgakopoulos-Soares","year":"2023","journal-title":"Nat Commun"},{"key":"pcbi.1011802.ref092","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.cell.2014.11.041","article-title":"Low affinity binding site clusters confer hox specificity and regulatory robustness","volume":"160","author":"J Crocker","year":"2015","journal-title":"Cell"},{"key":"pcbi.1011802.ref093","doi-asserted-by":"crossref","first-page":"5273","DOI":"10.1038\/s41467-022-32971-0","article-title":"Systematic analysis of low-affinity transcription factor binding site clusters in vitro and in vivo establishes their functional relevance","volume":"13","author":"A Shahein","year":"2022","journal-title":"Nat Commun"},{"key":"pcbi.1011802.ref094","doi-asserted-by":"crossref","first-page":"e60633","DOI":"10.1371\/journal.pone.0060633","article-title":"Sterile alpha motif containing 7 (samd7) is a novel crx-regulated transcriptional repressor in the retina.","volume":"8","author":"J Hlawatsch","year":"2013","journal-title":"PLoS One"},{"key":"pcbi.1011802.ref095","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abh2868","article-title":"Mutations in BCOR, a co-repressor of CRX\/OTX2, are associated with early-onset retinal degeneration.","volume":"8","author":"M Langou\u00ebt","year":"2022","journal-title":"Sci Adv."},{"key":"pcbi.1011802.ref096","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.febslet.2009.12.030","article-title":"Panky, a novel photoreceptor-specific ankyrin repeat protein, is a transcriptional cofactor that suppresses CRX-regulated photoreceptor genes","volume":"584","author":"R Sanuki","year":"2010","journal-title":"FEBS Lett"},{"key":"pcbi.1011802.ref097","doi-asserted-by":"crossref","first-page":"E11604","DOI":"10.1073\/pnas.1809454115","article-title":"The calculation of transcript flux ratios reveals single regulatory mechanisms capable of activation and repression","volume":"115","author":"EA Galburt","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1011802.ref098","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.cels.2023.02.003","article-title":"Transcriptional kinetic synergy: A complex landscape revealed by integrating modeling and synthetic biology","volume":"14","author":"R Martinez-Corral","year":"2023","journal-title":"Cell Syst"},{"key":"pcbi.1011802.ref099","article-title":"Pathogenic variants in CRX have distinct cis-regulatory effects on enhancers and silencers in photoreceptors.","author":"JL Shepherdson","year":"2023","journal-title":"bioRxiv"},{"key":"pcbi.1011802.ref100","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.celrep.2019.12.072","article-title":"Functional and Evolutionary Diversification of Otx2 and Crx in Vertebrate Retinal Photoreceptor and Bipolar Cell Development.","volume":"30","author":"H Yamamoto","year":"2020","journal-title":"Cell Rep"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1011802","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T00:00:00Z","timestamp":1706227200000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011802","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T13:39:04Z","timestamp":1706276344000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1011802"}},"subtitle":[],"editor":[{"given":"Jie","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,1,16]]},"references-count":100,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1011802","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.03.05.531194","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,16]]}}}