An encyclopedia of enhancer-gene regulatory interactions in the human genome.
| العنوان: | An encyclopedia of enhancer-gene regulatory interactions in the human genome. |
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| المؤلفون: | Gschwind AR; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA., Mualim KS; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Department of Plant Biology, Carnegie Institute of Science, Stanford, CA, USA., Karbalayghareh A; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Sheth MU; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA.; Department of Bioengineering, Stanford University, Stanford, CA, USA., Dey KK; Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Jagoda E; The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Nurtdinov RN; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain., Xi W; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Tan AS; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA., Jones H; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA., Ma XR; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA., Yao D; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Nasser J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Present Address: Department of Systems Biology, Harvard Medical School, Boston, MA, USA., Avsec Ž; Google DeepMind, London, UK., James BT; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA., Shamim MS; The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.; Department of Bioengineering, Rice University, Houston, TX, USA.; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA., Durand NC; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.; Department of Computer Science, Rice University, Houston, TX, USA., Rao SSP; The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Department of Medicine, University of California San Francisco, San Francisco, CA, USA.; Department of Structural Biology, Stanford University, Stanford, CA, USA., Mahajan R; The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.; Department of Biosciences, Rice University, Houston, TX, USA., Doughty BR; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Andreeva K; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Ulirsch JC; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Present Address: Artificial Intelligence Laboratory, Illumina, Inc., San Diego, CA, USA., Fan K; Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.; Present Address: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA., Perez EM; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Nguyen TC; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA., Kelley DR; Calico Life Sciences, South San Francisco, CA, USA., Finucane HK; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Moore JE; Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA., Weng Z; Program in Bioinformatics and Integrative Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA., Kellis M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA., Bassik MC; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Price AL; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Beer MA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Guigó R; Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain., Stamatoyannopoulos JA; Altius Institute for Biomedical Sciences, Seattle, WA, USA.; Clinical Research Division, Fred Hutch Cancer Center, Seattle, WA, USA., Lieberman Aiden E; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.; Department of Computer Science, Rice University, Houston, TX, USA., Greenleaf WJ; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Department of Applied Physics, Stanford University, Stanford, CA, USA., Leslie CS; Memorial Sloan Kettering Cancer Center, New York, NY, USA., Steinmetz LM; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Stanford Genome Technology Center, Palo Alto, CA, USA.; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany., Kundaje A; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Department of Computer Science, Stanford University, Stanford, CA, USA., Engreitz JM; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.; Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA.; The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 13. Date of Electronic Publication: 2023 Nov 13. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the impact of human genetic variation on disease 1-6 . Here we create and evaluate a resource of >13 million enhancer-gene regulatory interactions across 352 cell types and tissues, by integrating predictive models, measurements of chromatin state and 3D contacts, and largescale genetic perturbations generated by the ENCODE Consortium 7 . We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,411 elementgene pairs measured in CRISPR perturbation experiments, >30,000 fine-mapped eQTLs, and 569 fine-mapped GWAS variants linked to a likely causal gene. Using this framework, we develop a new predictive model, ENCODE-rE2G, that achieves state-of-the-art performance across multiple prediction tasks, demonstrating a strategy involving iterative perturbations and supervised machine learning to build increasingly accurate predictive models of enhancer regulation. Using the ENCODE-rE2G model, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, which reveals global properties of enhancer networks, identifies differences in the functions of genes that have more or less complex regulatory landscapes, and improves analyses to link noncoding variants to target genes and cell types for common, complex diseases. By interpreting the model, we find evidence that, beyond enhancer activity and 3D enhancer-promoter contacts, additional features guide enhancerpromoter communication including promoter class and enhancer-enhancer synergy. Altogether, these genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models, and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics. Competing Interests: Conflict of Interest Statement Z.A. is employed by Google DeepMind. J.C.U. is an employee of Illumina, Inc. D.R.K. is employed by Calico Life Sciences LLC. Z.W. co-founded Rgenta Therapeutics, and she serves as a scientific advisor for the company and is a member of its board. W.J.G. is an inventor on IP licensed by 10x Genomics. A.Kundaje is on the scientific advisory board of PatchBio, SerImmune and OpenTargets, was a consultant with Illumina, and owns shares in DeepGenomics, ImmunAI and Freenome. J.M.E. is a consultant and equity holder in Martingale Labs, Inc. and has received materials from 10x Genomics unrelated to this study. |
| References: | Am J Hum Genet. 2020 Feb 6;106(2):215-233. (PMID: 32032514) Nat Genet. 2023 Aug;55(8):1267-1276. (PMID: 37443254) Proc Natl Acad Sci U S A. 2014 May 27;111(21):E2191-9. (PMID: 24821768) Genome Res. 2013 May;23(5):777-88. (PMID: 23482648) Nature. 2017 Oct 11;550(7675):204-213. (PMID: 29022597) Genome Biol. 2017 Oct 20;18(1):193. (PMID: 29058599) Nature. 2012 Aug 2;488(7409):116-20. (PMID: 22763441) Elife. 2015 Aug 12;4:. (PMID: 26267217) Nat Genet. 2019 Dec;51(12):1664-1669. (PMID: 31784727) Genome Res. 2022 May;32(5):930-944. (PMID: 35396274) Nat Methods. 2021 Oct;18(10):1196-1203. (PMID: 34608324) Dev Cell. 2014 Sep 29;30(6):660-72. (PMID: 25220394) Nat Genet. 2016 Aug;48(8):895-903. (PMID: 27376235) Nature. 2018 Feb 8;554(7691):239-243. (PMID: 29420474) Genome Biol. 2023 Mar 27;24(1):56. (PMID: 36973806) Nat Genet. 2016 May;48(5):488-96. (PMID: 27064255) Science. 2016 Nov 11;354(6313):769-773. (PMID: 27708057) Elife. 2018 Aug 02;7:. (PMID: 30070637) Science. 2022 Sep 2;377(6610):1077-1085. (PMID: 35951677) Mol Metab. 2021 Dec;54:101388. (PMID: 34774811) Cell. 2014 Dec 18;159(7):1665-80. (PMID: 25497547) Nature. 2020 Aug;584(7820):244-251. (PMID: 32728217) J Biol Chem. 2022 Aug;298(8):102117. (PMID: 35691341) Nat Genet. 2016 Aug;48(8):904-911. (PMID: 27376239) Nat Biotechnol. 2017 Jun;35(6):561-568. (PMID: 28369033) Nat Struct Mol Biol. 2022 Dec;29(12):1148-1158. (PMID: 36482255) Mol Cell. 2023 Apr 6;83(7):1140-1152.e7. (PMID: 36931273) Nat Rev Genet. 2020 May;21(5):292-310. (PMID: 31988385) Nat Commun. 2018 Mar 5;9(1):943. (PMID: 29507293) Science. 2020 Sep 11;369(6509):1318-1330. (PMID: 32913098) Mol Cell. 2022 Jul 7;82(13):2519-2531.e6. (PMID: 35594855) Protein Sci. 2018 Jan;27(1):233-244. (PMID: 28940711) Genome Res. 2014 Jan;24(1):1-13. (PMID: 24196873) Cell. 2013 Nov 7;155(4):934-47. (PMID: 24119843) Nature. 2012 Sep 6;489(7414):75-82. (PMID: 22955617) Nature. 2012 Sep 6;489(7414):57-74. (PMID: 22955616) Cell. 2019 Mar 7;176(6):1516. (PMID: 30849375) Genome Biol. 2015 May 21;16:105. (PMID: 25994056) Nature. 2021 Feb;590(7845):300-307. (PMID: 33536621) Nat Methods. 2020 Jun;17(6):629-635. (PMID: 32483332) Cell. 2019 Jan 10;176(1-2):377-390.e19. (PMID: 30612741) Cell. 2012 Jan 20;148(1-2):84-98. (PMID: 22265404) Nature. 2015 Feb 19;518(7539):337-43. (PMID: 25363779) Nat Genet. 2023 Aug;55(8):1336-1346. (PMID: 37488417) Nature. 2011 May 5;473(7345):43-9. (PMID: 21441907) Science. 2012 Sep 7;337(6099):1190-5. (PMID: 22955828) Crit Rev Biochem Mol Biol. 2015;50(6):550-73. (PMID: 26446758) PLoS Genet. 2015 Feb 11;11(2):e1004935. (PMID: 25671638) Trends Cell Biol. 2014 Nov;24(11):695-702. (PMID: 25160912) Nature. 2021 May;593(7858):238-243. (PMID: 33828297) Nature. 2012 Sep 6;489(7414):109-13. (PMID: 22955621) Science. 2019 May 3;364(6439):. (PMID: 31048460) Nat Genet. 2016 Dec 28;49(1):2-3. (PMID: 28029159) Nature. 2022 Jul;607(7917):176-184. (PMID: 35594906) |
| معلومات مُعتمدة: | U24 HG009397 United States HG NHGRI NIH HHS; R00 HG012203 United States HG NHGRI NIH HHS; U01 HG009431 United States HG NHGRI NIH HHS; R35 HG011324 United States HG NHGRI NIH HHS; U01 HG012103 United States HG NHGRI NIH HHS; UM1 HG011972 United States HG NHGRI NIH HHS; U01 HG012069 United States HG NHGRI NIH HHS; T32 HG000044 United States HG NHGRI NIH HHS; K99 HG009917 United States HG NHGRI NIH HHS; U01 HG009380 United States HG NHGRI NIH HHS; U01 HG009395 United States HG NHGRI NIH HHS; R00 HG009917 United States HG NHGRI NIH HHS; U01 HG012009 United States HG NHGRI NIH HHS; R01 HG012367 United States HG NHGRI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; U41 HG006992 United States HG NHGRI NIH HHS; UM1 HG009436 United States HG NHGRI NIH HHS; U24 HG009446 United States HG NHGRI NIH HHS |
| تواريخ الأحداث: | Date Created: 20231128 Latest Revision: 20240515 |
| رمز التحديث: | 20240515 |
| مُعرف محوري في PubMed: | PMC10680627 |
| DOI: | 10.1101/2023.11.09.563812 |
| PMID: | 38014075 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.11.09.563812 |
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