[KSCI] Korea Science Citation Index Service

http://dx.doi.org/10.5808/gi.20073

Functional annotation of lung cancer-associated genetic variants by cell type-specific epigenome and long-range chromatin interactome

Lee, Andrew J. (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))
Jung, Inkyung (Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST))

Publication Information

Abstract

Functional interpretation of noncoding genetic variants associated with complex human diseases and traits remains a challenge. In an effort to enhance our understanding of common germline variants associated with lung cancer, we categorize regulatory elements based on eight major cell types of human lung tissue. Our results show that 21.68% of lung cancer-associated risk variants are linked to noncoding regulatory elements, nearly half of which are cell type-specific. Integrative analysis of high-resolution long-range chromatin interactome maps and single-cell RNA-sequencing data of lung tumors uncovers number of putative target genes of these variants and functionally relevant cell types, which display a potential biological link to cancer susceptibility. The present study greatly expands the scope of functional annotation of lung cancer-associated genetic risk factors and dictates probable cell types involved in lung carcinogenesis.

Keywords

3D chromatin interaction; cis-regulatory element; genome-wide association study; lung cancer; single-cell RNA sequencing; single nucleotide polymorphism;

Citations & Related Records

Reference

1	Sanyal A, Lajoie BR, Jain G, Dekker J. The long-range interaction landscape of gene promoters. Nature 2012;489:109-113. DOI
2	Buniello A, MacArthur JAL, Cerezo M, Harris LW, Hayhurst J, Malangone C, et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res 2019;47:D1005-D1012. DOI
3	Kim N, Kim HK, Lee K, Hong Y, Cho JH, Choi JW, et al. Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma. Nat Commun 2020;11:2285. DOI
4	Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol 2018;36:411-420. DOI
5	McKay JD, Hung RJ, Han Y, Zong X, Carreras-Torres R, Christiani DC, et al. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat Genet 2017;49:1126-1132. 28604730 DOI
6	Sato Y, Yamamoto N, Kunitoh H, Ohe Y, Minami H, Laird NM, et al. Genome-wide association study on overall survival of advanced non-small cell lung cancer patients treated with carboplatin and paclitaxel. J Thorac Oncol 2011;6:132-138. DOI
7	Byun J, Schwartz AG, Lusk C, Wenzlaff AS, de Andrade M, Mandal D, et al. Genome-wide association study of familial lung cancer. Carcinogenesis 2018;39:1135-1140. DOI
8	Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol 2008;9:R137. DOI
9	Lee Y, Yoon KA, Joo J, Lee D, Bae K, Han JY, et al. Prognostic implications of genetic variants in advanced non-small cell lung cancer: a genome-wide association study. Carcinogenesis 2013;34:307-313. DOI
10	Zhong X, Zhang W, Sun T. DDR1 promotes breast tumor growth by suppressing antitumor immunity. Oncol Rep 2019;42:2844-2854.
11	Gadiya M, Chakraborty G. Signaling by discoidin domain receptor 1 in cancer metastasis. Cell Adh Migr 2018;12:315-323.
12	Wang A, Chiou J, Poirion OB, Buchanan J, Valdez MJ, Verheyden JM, et al. Single-cell multiomic profiling of human lungs reveals cell-type-specific and age-dynamic control of SARS-CoV2 host genes. Elife 2020;9:e62522. DOI
13	Dixon JR, Jung I, Selvaraj S, Shen Y, Antosiewicz-Bourget JE, Lee AY, et al. Chromatin architecture reorganization during stem cell differentiation. Nature 2015;518:331-336. DOI
14	Niederriter AR, Varshney A, Parker SC, Martin DM. Super enhancers in cancers, complex disease, and developmental disorders. Genes (Basel) 2015;6:1183-1200. DOI
15	Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol 2010;28:1045-1048. DOI
16	Carullo NV, Day JJ. Genomic enhancers in brain health and disease. Genes (Basel) 2019;10:43. DOI
17	Lewinsky H, Barak AF, Huber V, Kramer MP, Radomir L, Sever L, et al. CD84 regulates PD-1/PD-L1 expression and function in chronic lymphocytic leukemia. J Clin Invest 2018;128:5465-5478. DOI
18	Ay F, Bailey TL, Noble WS. Statistical confidence estimation for Hi-C data reveals regulatory chromatin contacts. Genome Res 2014;24:999-1011. DOI
19	Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 2010;26:139-140. DOI
20	Sloan CA, Chan ET, Davidson JM, Malladi VS, Strattan JS, Hitz BC, et al. ENCODE data at the ENCODE portal. Nucleic Acids Res 2016;44:D726-D732. DOI
21	Davis CA, Hitz BC, Sloan CA, Chan ET, Davidson JM, Gabdank I, et al. The Encyclopedia of DNA elements (ENCODE): data portal update. Nucleic Acids Res 2018;46:D794-D801. DOI
22	Karnuta JM, Scacheri PC. Enhancers: bridging the gap between gene control and human disease. Hum Mol Genet 2018;27: R219-R227. DOI
23	Stenson PD, Mort M, Ball EV, Shaw K, Phillips A, Cooper DN. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 2014;133:1-9. DOI
24	Lettice LA, Heaney SJ, Purdie LA, Li L, de Beer P, Oostra BA, et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 2003;12:1725-1735. DOI
25	Jin F, Li Y, Dixon JR, Selvaraj S, Ye Z, Lee AY, et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 2013;503:290-294. DOI
26	Rao SS, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 2014; 159:1665-1680. DOI
27	Jung I, Schmitt A, Diao Y, Lee AJ, Liu T, Yang D, et al. A compendium of promoter-centered long-range chromatin interactions in the human genome. Nat Genet 2019;51:1442-1449. DOI
28	Yamashita R, Sugano S, Suzuki Y, Nakai K. DBTSS: DataBase of Transcriptional Start Sites progress report in 2012. Nucleic Acids Res 2012;40:D150-D154. DOI
29	Yang C, Stueve TR, Yan C, Rhie SK, Mullen DJ, Luo J, et al. Positional integration of lung adenocarcinoma susceptibility loci with primary human alveolar epithelial cell epigenomes. Epigenomics 2018;10:1167-1187. DOI
30	Yoon KA, Park JH, Han J, Park S, Lee GK, Han JY, et al. A genome-wide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population. Hum Mol Genet 2010;19:4948-4954. DOI
31	Shlyueva D, Stampfel G, Stark A. Transcriptional enhancers: from properties to genome-wide predictions. Nat Rev Genet 2014; 15:272-286. DOI