دورية أكاديمية
Regulatory genomic circuitry of human disease loci by integrative epigenomics.
العنوان: | Regulatory genomic circuitry of human disease loci by integrative epigenomics. |
---|---|
المؤلفون: | Boix CA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA, USA., James BT; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Park YP; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Meuleman W; Altius Institute for Biomedical Sciences, Seattle, WA, USA., Kellis M; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA. manoli@mit.edu.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. manoli@mit.edu. |
المصدر: | Nature [Nature] 2021 Feb; Vol. 590 (7845), pp. 300-307. Date of Electronic Publication: 2021 Feb 03. |
نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
مواضيع طبية MeSH: | Epigenomics*, Disease/*genetics , Epigenesis, Genetic/*genetics , Gene Regulatory Networks/*genetics , Genetic Loci/*genetics, Chromatin/genetics ; Enhancer Elements, Genetic/genetics ; Female ; Genome-Wide Association Study ; Humans ; Male ; Multifactorial Inheritance/genetics ; Organ Specificity/genetics ; Reproducibility of Results |
مستخلص: | Annotating the molecular basis of human disease remains an unsolved challenge, as 93% of disease loci are non-coding and gene-regulatory annotations are highly incomplete 1-3 . Here we present EpiMap, a compendium comprising 10,000 epigenomic maps across 800 samples, which we used to define chromatin states, high-resolution enhancers, enhancer modules, upstream regulators and downstream target genes. We used this resource to annotate 30,000 genetic loci that were associated with 540 traits 4 , predicting trait-relevant tissues, putative causal nucleotide variants in enriched tissue enhancers and candidate tissue-specific target genes for each. We partitioned multifactorial traits into tissue-specific contributing factors with distinct functional enrichments and disease comorbidity patterns, and revealed both single-factor monotropic and multifactor pleiotropic loci. Top-scoring loci frequently had multiple predicted driver variants, converging through multiple enhancers with a common target gene, multiple genes in common tissues, or multiple genes and multiple tissues, indicating extensive pleiotropy. Our results demonstrate the importance of dense, rich, high-resolution epigenomic annotations for the investigation of complex traits. |
التعليقات: | Comment in: Cardiovasc Res. 2021 May 25;117(6):e73-e75. (PMID: 33914859) Comment in: Signal Transduct Target Ther. 2021 May 8;6(1):179. (PMID: 33966052) |
References: | Visscher, P. M. et al. 10 Years of GWAS discovery: biology, function, and translation. Am. J. Hum. Genet. 101, 5–22 (2017). (PMID: 28686856550187210.1016/j.ajhg.2017.06.005) Gallagher, M. D. & Chen-Plotkin, A. S. The post-GWAS era: from association to function. Am. J. Hum. Genet. 102, 717–730 (2018). (PMID: 29727686598673210.1016/j.ajhg.2018.04.002) Ward, L. D. & Kellis, M. Interpreting noncoding genetic variation in complex traits and human disease. Nat. Biotechnol. 30, 1095–1106 (2012). (PMID: 23138309370346710.1038/nbt.2422) Buniello, A. et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 47, D1005–D1012 (2019). (PMID: 3044543410.1093/nar/gky1120) ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012). (PMID: 10.1038/nature11247) Roadmap Epigenomics Consortium et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015). (PMID: 453001010.1038/nature14248) Stunnenberg, H. G. & Hirst, M. The International Human Epigenome Consortium. a blueprint for scientific collaboration and discovery. Cell 167, 1145–1149 (2016). (PMID: 2786323210.1016/j.cell.2016.11.007) Genomics of Gene Regulation. Genome.gov https://www.genome.gov/Funded-Programs-Projects/Genomics-of-Gene-Regulation (accessed 28 September 2020). Ernst, J. & Kellis, M. Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat. Biotechnol. 28, 817–825 (2010). (PMID: 20657582291962610.1038/nbt.1662) Hoffman, M. M. et al. Unsupervised pattern discovery in human chromatin structure through genomic segmentation. Nat. Methods 9, 473–476 (2012). (PMID: 22426492334053310.1038/nmeth.1937) Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011). (PMID: 21441907308877310.1038/nature09906) Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190–1195 (2012). (PMID: 22955828377152110.1126/science.1222794) Cantor, R. M., Lange, K. & Sinsheimer, J. S. Prioritizing GWAS results: a review of statistical methods and recommendations for their application. Am. J. Hum. Genet. 86, 6–22 (2010). (PMID: 20074509280174910.1016/j.ajhg.2009.11.017) Farh, K. K.-H. et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015). (PMID: 2536377910.1038/nature13835) Dimas, A. S., Deutsch, S. & Stranger, B. E. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325, 1246–1250 (2009). (PMID: 19644074286721810.1126/science.1174148) Ward, L. D. & Kellis, M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930–D934 (2012). (PMID: 2206485110.1093/nar/gkr917) Pickrell, J. K. Joint analysis of functional genomic data and genome-wide association studies of 18 human traits. Am. J. Hum. Genet. 94, 559–573 (2014). (PMID: 24702953398052310.1016/j.ajhg.2014.03.004) Gusev, A. et al. Partitioning heritability of regulatory and cell-type-specific variants across 11 common diseases. Am. J. Hum. Genet. 95, 535–552 (2014). (PMID: 25439723422559510.1016/j.ajhg.2014.10.004) Finucane, H. K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015). (PMID: 26414678462628510.1038/ng.3404) Ernst, J. & Kellis, M. Large-scale imputation of epigenomic datasets for systematic annotation of diverse human tissues. Nat. Biotechnol. 33, 364–376 (2015). (PMID: 25690853451230610.1038/nbt.3157) Li, D., Hsu, S., Purushotham, D., Sears, R. L. & Wang, T. Epigenome browser update 2019. Nucleic Acids Res. 47, W158–W165 (2019). (PMID: 31165883660245910.1093/nar/gkz348) Calo, E. & Wysocka, J. Modification of enhancer chromatin: what, how, and why? Mol. Cell 49, 825–837 (2013). (PMID: 2347360110.1016/j.molcel.2013.01.038) Becker, J. S., Nicetto, D. & Zaret, K. S. H3K9me3-dependent heterochromatin: barrier to cell fate changes. Trends Genet. 32, 29–41 (2016). (PMID: 2667538410.1016/j.tig.2015.11.001) Meuleman, W. et al. Index and biological spectrum of human DNase I hypersensitive sites. Nature 584, 244–251 (2020). (PMID: 32728217742267710.1038/s41586-020-2559-3) ENCODE Project Consortium et al. Expanded encyclopaedias of DNA elements in the human and mouse genomes. Nature 583, 699–710 (2020). (PMID: 10.1038/s41586-020-2493-4) Vierstra, J. et al. Global reference mapping of human transcription factor footprints. Nature 583, 729–736 (2020). (PMID: 32728250741082910.1038/s41586-020-2528-x) Laslo, P. et al. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126, 755–766 (2006). (PMID: 1692339410.1016/j.cell.2006.06.052) Blackshear, P. J. et al. Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4. Development 130, 4539–4552 (2003). (PMID: 1292558210.1242/dev.00661) Olson, J. M. et al. NeuroD2 is necessary for development and survival of central nervous system neurons. Dev. Biol. 234, 174–187 (2001). (PMID: 1135602810.1006/dbio.2001.0245) Katz, J. P. et al. The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon. Development 129, 2619–2628 (2002). (PMID: 1201529010.1242/dev.129.11.2619) Jacquemin, P., Martial, J. A. & Davidson, I. Human TEF-5 is preferentially expressed in placenta and binds to multiple functional elements of the human chorionic somatomammotropin-B gene enhancer. J. Biol. Chem. 272, 12928–12937 (1997). (PMID: 914889810.1074/jbc.272.20.12928) Tanaka, T. et al. Dysregulated expression of P1 and P2 promoter-driven hepatocyte nuclear factor-4α in the pathogenesis of human cancer. J. Pathol. 208, 662–672 (2006). (PMID: 1640063110.1002/path.1928) Wagner, E. F. & Eferl, R. Fos/AP-1 proteins in bone and the immune system. Immunol. Rev. 208, 126–140 (2005). (PMID: 1631334510.1111/j.0105-2896.2005.00332.x) MacArthur, J. et al. The new NHGRI-EBI catalog of published genome-wide association studies (GWAS catalog). Nucleic Acids Res. 45, D896–D901 (2017). (PMID: 2789967010.1093/nar/gkw1133) Michailidou, K. et al. Association analysis identifies 65 new breast cancer risk loci. Nature 551, 92–94 (2017). (PMID: 29059683579858810.1038/nature24284) Goes, F. S. et al. Genome-wide association study of schizophrenia in Ashkenazi Jews. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 168, 649–659 (2015). (PMID: 2619876410.1002/ajmg.b.32349) Lupien, M., Markowitz, S. & Scacheri, P. C. Combinatorial effects of multiple enhancer variants in linkage disequilibrium dictate levels of gene expression to confer susceptibility to common traits. Genome Res. 24, 1–13 (2014). (PMID: 24196873387585010.1101/gr.164079.113) Henstridge, C. M., Hyman, B. T. & Spires-Jones, T. L. Beyond the neuron–cellular interactions early in Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 20, 94–108 (2019). (PMID: 30643230654507010.1038/s41583-018-0113-1) Winkler, T. W. et al. The influence of age and sex on genetic associations with adult body size and shape: a large-scale genome-wide interaction study. PLoS Genet. 11, e1005378 (2015). (PMID: 26426971459137110.1371/journal.pgen.1005378) van der Harst, P. & Verweij, N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ. Res. 122, 433–443 (2018). (PMID: 29212778580527710.1161/CIRCRESAHA.117.312086) Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003). (PMID: 1273069710.1038/ng1161) Busnelli, M. et al. Liver-specific deletion of the Plpp3 gene alters plasma lipid composition and worsens atherosclerosis in apoE −/− mice. Sci. Rep. 7, 44503 (2017). (PMID: 28291223534960910.1038/srep44503) Lappegård, K. T. et al. A vital role for complement in heart disease. Mol. Immunol. 61, 126–134 (2014). (PMID: 2503763310.1016/j.molimm.2014.06.036) Arad, M., Seidman, C. E. & Seidman, J. G. AMP-activated protein kinase in the heart: role during health and disease. Circ. Res. 100, 474–488 (2007). (PMID: 1733243810.1161/01.RES.0000258446.23525.37) Lee, D. et al. A method to predict the impact of regulatory variants from DNA sequence. Nat. Genet. 47, 955–961 (2015). (PMID: 26075791452074510.1038/ng.3331) Moyerbrailean, G. A. et al. Which genetics variants in DNase-seq footprints are more likely to alter binding? PLoS Genet. 12, e1005875 (2016). (PMID: 26901046476426010.1371/journal.pgen.1005875) Karimzadeh, M., Ernst, C., Kundaje, A. & Hoffman, M. M. Umap and Bismap: quantifying genome and methylome mappability. Nucleic Acids Res. 46, e120 (2018). (PMID: 301696596237805) Rosenbloom, K. R. et al. The UCSC Genome Browser database: 2015 update. Nucleic Acids Res. 43, D670–D681 (2015). (PMID: 2542837410.1093/nar/gku1177) Kharchenko, P. V., Tolstorukov, M. Y. & Park, P. J. Design and analysis of ChIP-seq experiments for DNA-binding proteins. Nat. Biotechnol. 26, 1351–1359 (2008). (PMID: 19029915259770110.1038/nbt.1508) Feng, J., Liu, T., Qin, B., Zhang, Y. & Liu, X. S. Identifying ChIP-seq enrichment using MACS. Nat. Protocols 7, 1728–1740 (2012). (PMID: 2293621510.1038/nprot.2012.101) Gu, Z., Gu, L., Eils, R., Schlesner, M. & Brors, B. circlize implements and enhances circular visualization in R. Bioinformatics 30, 2811–2812 (2014). (PMID: 2493013910.1093/bioinformatics/btu393) Leland, M., Healy, J. & Melville, J. Umap: uniform manifold approximation and projection for dimension reduction. Preprint at https://arxiv.org/abs/1802.03426 (2018). McLean, C. Y. et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501 (2010). (PMID: 20436461484023410.1038/nbt.1630) Kheradpour, P. & Kellis, M. Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments. Nucleic Acids Res. 42, 2976–2987 (2014). (PMID: 2433514610.1093/nar/gkt1249) Khan, A. et al. JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. Nucleic Acids Res. 46, D1284 (2018). (PMID: 2916143310.1093/nar/gkx1188) Kulakovskiy, I. V. et al. HOCOMOCO: towards a complete collection of transcription factor binding models for human and mouse via large-scale ChIP-seq analysis. Nucleic Acids Res. 46, D252–D259 (2018). (PMID: 2914046410.1093/nar/gkx1106) Jolma, A. et al. DNA-binding specificities of human transcription factors. Cell 152, 327–339 (2013). (PMID: 2333276410.1016/j.cell.2012.12.009) Liu, Y., Sarkar, A., Kheradpour, P., Ernst, J. & Kellis, M. Evidence of reduced recombination rate in human regulatory domains. Genome Biol. 18, 193 (2017). (PMID: 29058599565159610.1186/s13059-017-1308-x) Moore, J. E., Pratt, H. E., Purcaro, M. J. & Weng, Z. A curated benchmark of enhancer–gene interactions for evaluating enhancer–target gene prediction methods. Genome Biol. 21, 17 (2020). (PMID: 31969180697730110.1186/s13059-019-1924-8) Fulco, C. P. et al. Activity-by-contact model of enhancer-promoter regulation from thousands of CRISPR perturbations. Nat. Genet. 51, 1664–1669 (2019). (PMID: 31784727688658510.1038/s41588-019-0538-0) Yu, G., Wang, L.-G., Han, Y. & He, Q.-Y. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16, 284–287 (2012). (PMID: 22455463333937910.1089/omi.2011.0118) Csardi, G. & Nepusz, T. The igraph software package for complex network research. InterJournal Complex Syst. 1695, 1–9 (2006). Chang, W. et al. shiny: web application framework for R. R package version 1 (2017). The Gene Ontology Consortium. Gene ontology: tool for the unification of biology. Nat. Genet. 25, 25–29 (2000). (PMID: 303741910.1038/75556) |
معلومات مُعتمدة: | HG008155 United States NH NIH HHS; U41 HG007234 United States HG NHGRI NIH HHS; MH109978 United States NH NIH HHS; MH119509 United States NH NIH HHS; U24 HG009446 United States HG NHGRI NIH HHS; GM087237 United States NH NIH HHS; HG007234 United States NH NIH HHS; R01 MH109978 United States MH NIMH NIH HHS; U01 MH119509 United States MH NIMH NIH HHS; R01 AG058002 United States AG NIA NIH HHS; R01 HG008155 United States HG NHGRI NIH HHS; R35 HG011317 United States HG NHGRI NIH HHS; R01 GM113708 United States GM NIGMS NIH HHS; U01 HG007610 United States HG NHGRI NIH HHS; HG009446 United States NH NIH HHS; HG009088 United States NH NIH HHS; T32 GM087237 United States GM NIGMS NIH HHS; AG058002 United States NH NIH HHS; HG007610 United States NH NIH HHS; GM113708 United States NH NIH HHS; U01 HG009088 United States HG NHGRI NIH HHS |
المشرفين على المادة: | 0 (Chromatin) |
تواريخ الأحداث: | Date Created: 20210204 Date Completed: 20210309 Latest Revision: 20230129 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC7875769 |
DOI: | 10.1038/s41586-020-03145-z |
PMID: | 33536621 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1476-4687 |
---|---|
DOI: | 10.1038/s41586-020-03145-z |