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Cited by 36Genomics and Chromatin DynamicsGenetic Associations and EpidemiologyChromatin Remodeling and Cancer

Analysis of Promoter-Associated Chromatin Interactions Reveals Biologically Relevant Candidate Target Genes at Endometrial Cancer Risk Loci

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O’Mara, Tracy A., Spurdle, Amanda B., Glubb, Dylan M., Endometrial Cancer Association Consortium·2019·Cancers
DOI 10.3390/cancers11101440PMC PMC6826789

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Abstract

The identification of target genes at genome-wide association study (GWAS) loci is a major obstacle for GWAS follow-up. To identify candidate target genes at the 16 known endometrial cancer GWAS risk loci, we performed HiChIP chromatin looping analysis of endometrial cell lines. To enrich for enhancer–promoter interactions, a mechanism through which GWAS variation may target genes, we captured chromatin loops associated with H3K27Ac histone, characteristic of promoters and enhancers. Analysis of HiChIP loops contacting promoters revealed enrichment for endometrial cancer GWAS heritability and intersection with endometrial cancer risk variation identified 103 HiChIP target genes at 13 risk loci. Expression of four HiChIP target genes (SNX11, SRP14, HOXB2 and BCL11A) was associated with risk variation, providing further evidence for their targeting. Network analysis functionally prioritized a set of proteins that interact with those encoded by HiChIP target genes, and this set was enriched for pan-cancer and endometrial cancer drivers. Lastly, HiChIP target genes and prioritized interacting proteins were over-represented in pathways related to endometrial cancer development. In summary, we have generated the first global chromatin looping data from normal and tumoral endometrial cells, enabling analysis of all known endometrial cancer risk loci and identifying biologically relevant candidate target genes.

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  • Using techniques with antibodies to enhancer- and promoter-associated histone modifications or RNA polymerase has revealed large numbers of 3D enhancer-promoter contacts.

    “Using these techniques with antibodies to enhancer- and promoter-associated histone modifications or those to RNA polymerase has also revealed large numbers of 3D enhancer–promoter contacts [244, 295–301].”

    From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [298]

    The Methods (§4.3) describe using an H3K27Ac antibody, and the Results (§2.1) report 66,092–449,157 chromatin loops per cell line, with 35%–40% contacting a promoter. This supports the histone-modification example and the large number of contacts, but the paper does not report using antibodies to RNA polymerase. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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  1. [1]O’Mara T.A. Glubb D.M. Amant F. Annibali D. Ashton K. Attia J. Auer P.L. Beckmann M.W. Black A. Bolla M.K. Identification of nine new susceptibility loci for endometrial cancer Nat. Commun. 2018 9 3166 10.1038/s41467-018-05427-7 30093612 PMC6085317 · DOI
  2. [2]Cheng T.H. Thompson D.J. O’Mara T.A. Painter J.N. Glubb D.M. Flach S. Lewis A. French J.D. Freeman-Mills L. Church D. Five endometrial cancer risk loci identified through genome-wide association analysis Nat. Genet. 2016 48 667 674 10.1038/ng.3562 27135401 PMC4907351 · DOI
  3. [3]Spurdle A.B. Thompson D.J. Ahmed S. Ferguson K. Healey C.S. O’Mara T. Walker L.C. Montgomery S.B. Dermitzakis E.T. Fahey P. Genome-wide association study identifies a common variant associated with risk of endometrial cancer Nat. Genet. 2011 43 451 454 10.1038/ng.812 21499250 PMC3770523 · DOI
  4. [4]O’Mara T.A. Glubb D.M. Kho P.F. Thompson D.J. Spurdle A. Genome-wide association studies of endometrial cancer: Latest developments and future directions Cancer Epidemiol. Prev. Biomark. 2019 28 1095 1102 10.1158/1055-9965.EPI-18-1031 31040137 · DOI
  5. [5]Thompson D.J. O’Mara T.A. Glubb D.M. Painter J.N. Cheng T. Folkerd E. Doody D. Dennis J. Webb P.M. ANECS Group CYP19A1 fine-mapping and Mendelian randomization: Estradiol is causal for endometrial cancer Endocr. Relat. Cancer 2016 23 77 91 10.1530/ERC-15-0386 26574572 PMC4697192 · DOI
  6. [6]Key T.J. Pike M.C. The dose-effect relationship between ‘unopposed’ oestrogens and endometrial mitotic rate: Its central role in explaining and predicting endometrial cancer risk Br. J. Cancer 1988 57 205 212 10.1038/bjc.1988.44 3358913 PMC2246441 · DOI
  7. [7]Antunes C.M. Strolley P.D. Rosenshein N.B. Davies J.L. Tonascia J.A. Brown C. Burnett L. Rutledge A. Pokempner M. Garcia R. Endometrial cancer and estrogen use. Report of a large case-control study N. Engl. J. Med. 1979 300 9 13 10.1056/NEJM197901043000103 213722 · DOI
  8. [8]Glubb D.M. Johnatty S.E. Quinn M.C.J. O’Mara T.A. Tyrer J.P. Gao B. Fasching P.A. Beckmann M.W. Lambrechts D. Vergote I. Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci Oncotarget 2017 10.18632/oncotarget.18501 29029385 PMC5630285 · DOI
  9. [9]Glubb D.M. Maranian M.J. Michailidou K. Pooley K.A. Meyer K.B. Kar S. Carlebur S. O’Reilly M. Betts J.A. Hillman K.M. Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1 Am. J. Hum. Genet. 2015 96 5 20 10.1016/j.ajhg.2014.11.009 25529635 PMC4289692 · DOI
  10. [10]Michailidou K. Lindstrom S. Dennis J. Beesley J. Hui S. Kar S. Lemacon A. Soucy P. Glubb D. Rostamianfar A. Association analysis identifies 65 new breast cancer risk loci Nature 2017 551 92 94 10.1038/nature24284 29059683 PMC5798588 · DOI
  11. [11]Gallagher M.D. Chen-Plotkin A.S. The post-GWAS era: From association to function Am. J. Hum. Genet. 2018 102 717 730 10.1016/j.ajhg.2018.04.002 29727686 PMC5986732 · DOI · Paper page
  12. [13]Davies J.O. Oudelaar A.M. Higgs D.R. Hughes J.R. How best to identify chromosomal interactions: A comparison of approaches Nat. Methods 2017 14 125 134 10.1038/nmeth.4146 28139673 · DOI
  13. [14]Mumbach M.R. Rubin A.J. Flynn R.A. Dai C. Khavari P.A. Greenleaf W.J. Chang H.Y. HiChIP: Efficient and sensitive analysis of protein-directed genome architecture Nat. Methods 2016 13 919 922 10.1038/nmeth.3999 27643841 PMC5501173 · DOI · Paper page
  14. [15]Phelan C.M. Kuchenbaecker K.B. Tyrer J.P. Kar S.P. Lawrenson K. Winham S.J. Dennis J. Pirie A. Riggan M.J. Chornokur G. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer Nat. Genet. 2017 49 680 691 10.1038/ng.3826 28346442 PMC5612337 · DOI
  15. [16]Dadaev T. Saunders E.J. Newcombe P.J. Anokian E. Leongamornlert D.A. Brook M.N. Cieza-Borrella C. Mijuskovic M. Wakerell S. Olama A.A.A. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants Nat. Commun. 2018 9 2256 10.1038/s41467-018-04109-8 29892050 PMC5995836 · DOI
  16. [17]Jiang X. Finucane H.K. Schumacher F.R. Schmit S.L. Tyrer J.P. Han Y. Michailidou K. Lesseur C. Kuchenbaecker K.B. Dennis J. Shared heritability and functional enrichment across six solid cancers Nat. Commun. 2019 10 431 10.1038/s41467-018-08054-4 30683880 PMC6347624 · DOI
  17. [18]Jeng M.Y. Mumbach M.R. Granja J.M. Satpathy A.T. Chang H.Y. Chang A.L.S. Enhancer connectome nominates target genes of inherited risk variants from inflammatory skin disorders J. Investig. Dermatol. 2019 139 605 614 10.1016/j.jid.2018.09.011 30315781 · DOI
  18. [19]Kandoth C. Schultz N. Cherniack A.D. Akbani R. Liu Y. Shen H. Robertson A.G. Pashtan I. Shen R. Benz C.C. Integrated genomic characterization of endometrial carcinoma Nature 2013 497 67 73 10.1038/nature12113 23636398 PMC3704730 · DOI · Paper page
  19. [20]Bordoloi D. Banik K. Shabnam B. Padmavathi G. Monisha J. Arfuso F. Dharmarajan A. Mao X. Lim L.H.K. Wang L. TIPE family of proteins and its implications in different chronic diseases Int. J. Mol. Sci. 2018 19 2974 10.3390/ijms19102974 PMC6213092 30274259 · DOI
  20. [21]Oberst M.D. Chen L.Y. Kiyomiya K. Williams C.A. Lee M.S. Johnson M.D. Dickson R.B. Lin C.Y. HAI-1 regulates activation and expression of matriptase, a membrane-bound serine protease Am. J. Physiol. Cell Physiol. 2005 289 C462 C470 10.1152/ajpcell.00076.2005 15800053 · DOI
  21. [23]Lim Y.W. Chen-Harris H. Mayba O. Lianoglou S. Wuster A. Bhangale T. Khan Z. Mariathasan S. Daemen A. Reeder J. Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration Proc. Natl. Acad. Sci. USA 2018 115 E11701 E11710 10.1073/pnas.1804506115 30463956 PMC6294879 · DOI
  22. [25]Gibson W.J. Hoivik E.A. Halle M.K. Taylor-Weiner A. Cherniack A.D. Berg A. Holst F. Zack T.I. Werner H.M. Staby K.M. The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis Nat. Genet. 2016 48 848 855 10.1038/ng.3602 27348297 PMC4963271 · DOI
  23. [26]Hanahan D. Weinberg R.A. Hallmarks of cancer: The next generation Cell 2011 144 646 674 10.1016/j.cell.2011.02.013 21376230 · DOI · Paper page
  24. [27]Pritchard J.E. O’Mara T.A. Glubb D.M. Enhancing the promise of drug repositioning through genetics Front. Pharmacol. 2017 8 896 10.3389/fphar.2017.00896 29270124 PMC5724196 · DOI
  25. [28]Liu T. Li J. Liu Y. Qu Y. Li A. Li C. Zhang Q. Wu W. Li J. Liu Y. SNX11 identified as an essential host factor for SFTS virus infection by CRISPR knockout screening Virol. Sin. 2019 10.1007/s12250-019-00141-0 PMC6814687 31215001 · DOI
  26. [29]Joyal J.S. Nim S. Zhu T. Sitaras N. Rivera J.C. Shao Z. Sapieha P. Hamel D. Sanchez M. Zaniolo K. Subcellular localization of coagulation factor II receptor-like 1 in neurons governs angiogenesis Nat. Med. 2014 20 1165 1173 10.1038/nm.3669 25216639 · DOI
  27. [30]Barrow J.R. Capecchi M.R. Targeted disruption of the Hoxb-2 locus in mice interferes with expression of Hoxb-1 and Hoxb-4 Development 1996 122 3817 3828 9012503
  28. [31]Nodale C. Ceccarelli S. Giuliano M. Cammarota M. D’Amici S. Vescarelli E. Maffucci D. Bellati F. Panici P.B. Romano F. Gene expression profile of patients with Mayer-Rokitansky-Küster-Hauser syndrome: New insights into the potential role of developmental pathways PLoS ONE 2014 9 e91010 10.1371/journal.pone.0091010 24608967 PMC3946625 · DOI
  29. [32]Lindblad O. Chougule R.A. Moharram S.A. Kabir N.N. Sun J. Kazi J.U. Ronnstrand L. The role of HOXB2 and HOXB3 in acute myeloid leukemia Biochem. Biophys. Res. Commun. 2015 467 742 747 10.1016/j.bbrc.2015.10.071 26482852 · DOI
  30. [33]Boimel P.J. Cruz C. Segall J.E. A functional in vivo screen for regulators of tumor progression identifies HOXB2 as a regulator of tumor growth in breast cancer Genomics 2011 98 164 172 10.1016/j.ygeno.2011.05.011 21672623 PMC3165059 · DOI
  31. [34]Berger A. Ivanova E. Gareau C. Scherrer A. Mazroui R. Strub K. Direct binding of the Alu binding protein dimer SRP9/14 to 40S ribosomal subunits promotes stress granule formation and is regulated by Alu RNA Nucleic Acids Res. 2014 42 11203 11217 10.1093/nar/gku822 25200073 PMC4176187 · DOI
  32. [35]Donnelly N. Gorman A.M. Gupta S. Samali A. The eIF2α kinases: Their structures and functions Cell. Mol. Life Sci. 2013 70 3493 3511 10.1007/s00018-012-1252-6 23354059 PMC11113696 · DOI
  33. [36]El-Naggar A.M. Sorensen P.H. Translational control of aberrant stress responses as a hallmark of cancer J. Pathol. 2018 244 650 666 10.1002/path.5030 29293271 · DOI
  34. [38]Khaled W.T. Choon Lee S. Stingl J. Chen X. Raza Ali H. Rueda O.M. Hadi F. Wang J. Yu Y. Chin S.F. BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells Nat. Commun. 2015 6 5987 10.1038/ncomms6987 25574598 PMC4338552 · DOI
  35. [39]Lazarus K.A. Hadi F. Zambon E. Bach K. Santolla M.F. Watson J.K. Correia L.L. Das M. Ugur R. Pensa S. BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma Nat. Commun. 2018 9 3327 10.1038/s41467-018-05790-5 30127402 PMC6102279 · DOI
  36. [40]Park S.Y. Lee S.-J. Cho H.J. Kim J.-T. Yoon H.R. Lee K.H. Kim B.Y. Lee Y. Lee H.G. Epsilon-globin HBE1 enhances radiotherapy resistance by down-regulating BCL11A in colorectal cancer cells Cancers 2019 11 498 10.3390/cancers11040498 PMC6521047 30965648 · DOI
  37. [41]Huang H.T. Chen S.M. Pan L.B. Yao J. Ma H.T. Loss of function of SWI/SNF chromatin remodeling genes leads to genome instability of human lung cancer Oncol. Rep. 2015 33 283 291 10.3892/or.2014.3584 25370573 · DOI
  38. [42]Darda L. Hakami F. Morgan R. Murdoch C. Lambert D.W. Hunter K.D. The role of HOXB9 and miR-196a in head and neck squamous cell carcinoma PLoS ONE 2015 10 e0122285 10.1371/journal.pone.0122285 25860510 PMC4393232 · DOI
  39. [43]Milevskiy M.J.G. Gujral U. Del Lama Marques C. Stone A. Northwood K. Burke L.J. Gee J.M.W. Nephew K. Clark S. Brown M.A. MicroRNA-196a is regulated by ER and is a prognostic biomarker in ER+ breast cancer Br. J. Cancer 2019 120 621 632 10.1038/s41416-019-0395-8 30783203 PMC6461839 · DOI
  40. [44]Meng X. Jin-Cheng G. Jue Z. Quan-Fu M. Bin Y. Xu-Feng W. Protein-coding genes, long non-coding RNAs combined with microRNAs as a novel clinical multi-dimension transcriptome signature to predict prognosis in ovarian cancer Oncotarget 2017 8 72847 72859 10.18632/oncotarget.20457 29069830 PMC5641173 · DOI
  41. [45]Hao Y. Wang J. Zhao L. The effect and mechanism of miR196a in HepG2 cell Biomed. Pharmacother. 2015 72 1 5 10.1016/j.biopha.2014.10.032 26054667 · DOI
  42. [46]Xu H. Li G. Yue Z. Li C. HCV core protein-induced upregulation of microRNA-196a promotes aberrant proliferation in hepatocellular carcinoma by targeting FOXO1 Mol. Med. Rep. 2016 13 5223 5229 10.3892/mmr.2016.5159 27108614 · DOI
  43. [47]Chen H. Fan Y. Xu W. Chen J. Meng Y. Fang D. Wang J. Exploration of miR-1202 and miR-196a in human endometrial cancer based on high throughout gene screening analysis Oncol. Rep. 2017 37 3493 3501 10.3892/or.2017.5596 28440476 · DOI
  44. [48]Nead K.T. Sharp S.J. Thompson D.J. Painter J.N. Savage D.B. Semple R.K. Barker A. Perry J.R. Attia J. Dunning A.M. Evidence of a causal association between insulinemia and endometrial cancer: A mendelian randomization analysis J. Natl. Cancer Inst. 2015 107 10.1093/jnci/djv178 PMC4572886 26134033 · DOI
  45. [49]Painter J.N. O’Mara T.A. Marquart L. Webb P.M. Attia J. Medland S.E. Cheng T. Dennis J. Holliday E.G. McEvoy M. Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer Cancer Epidemiol. Prev. Biomark. 2016 25 1503 1510 10.1158/1055-9965.EPI-16-0147 PMC5093082 27550749 · DOI
  46. [50]Lotta L.A. Wittemans L.B.L. Zuber V. Stewart I.D. Sharp S.J. Luan J. Day F.R. Li C. Bowker N. Cai L. Association of genetic variants related to gluteofemoral vs abdominal fat distribution with type 2 diabetes, coronary disease, and cardiovascular risk factors Jama 2018 320 2553 2563 10.1001/jama.2018.19329 30575882 PMC6583513 · DOI · Paper page
  47. [52]Hewitt S.C. Deroo B.J. Hansen K. Collins J. Grissom S. Afshari C.A. Korach K.S. Estrogen receptor-dependent genomic responses in the uterus mirror the biphasic physiological response to estrogen Mol. Endocrinol. 2003 17 2070 2083 10.1210/me.2003-0146 12893882 · DOI
  48. [53]Gründker C. Günthert A.R. Emons G. Hormonal heterogeneity of endometrial cancer Innovative Endocrinology of Cancer Berstein L.M. Santen R.J. Springer New York, NY, USA 2008 166 188 10.1007/978-0-387-78818-0_11 18637491 · DOI
  49. [54]Belaghzal H. Dekker J. Gibcus J.H. Hi-C 2.0: An optimized Hi-C procedure for high-resolution genome-wide mapping of chromosome conformation Methods 2017 123 56 65 10.1016/j.ymeth.2017.04.004 28435001 PMC5522765 · DOI
  50. [55]Servant N. Varoquaux N. Lajoie B.R. Viara E. Chen C.-J. Vert J.-P. Heard E. Dekker J. Barillot E. HiC-Pro: An optimized and flexible pipeline for Hi-C data processing Genome Biol. 2015 16 259 10.1186/s13059-015-0831-x 26619908 PMC4665391 · DOI · Paper page
  51. [56]Lareau C.A. Aryee M.J. hichipper: A preprocessing pipeline for calling DNA loops from HiChIP data Nat. Methods 2018 15 155 156 10.1038/nmeth.4583 29489746 PMC10572103 · DOI
  52. [57]Phanstiel D.H. Boyle A.P. Heidari N. Snyder M.P. Mango: A bias-correcting ChIA-PET analysis pipeline Bioinformatics 2015 31 3092 3098 10.1093/bioinformatics/btv336 26034063 PMC4592333 · DOI
  53. [58]Bulik-Sullivan B.K. Loh P.R. Finucane H.K. Ripke S. Yang J. Patterson N. Daly M.J. Price A.L. Neale B.M. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies Nat. Genet. 2015 47 291 295 10.1038/ng.3211 25642630 PMC4495769 · DOI · Paper page
  54. [59]Finucane H.K. Bulik-Sullivan B. Gusev A. Trynka G. Reshef Y. Loh P.R. Anttila V. Xu H. Zang C. Farh K. Partitioning heritability by functional annotation using genome-wide association summary statistics Nat. Genet. 2015 47 1228 1235 10.1038/ng.3404 26414678 PMC4626285 · DOI · Paper page
  55. [60]Tang Z. Kang B. Li C. Chen T. Zhang Z. GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis Nucleic Acids Res. 2019 47 W556 W560 10.1093/nar/gkz430 31114875 PMC6602440 · DOI
  56. [61]Chen J. Bardes E.E. Aronow B.J. Jegga A.G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization Nucleic Acids Res. 2009 37 W305 W311 10.1093/nar/gkp427 19465376 PMC2703978 · DOI · Paper page

Authors
O’Mara, T. A., Spurdle, A. B., Glubb, D. M., & Endometrial Cancer Association Consortium
Affiliations
QIMR Berghofer Medical Research Institute (AU)
Corresponding author
Glubb, Dylan M.
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2019-09-26
Volume
11
Issue
10
Pages
1440
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers11101440
PMC
PMC6826789
OpenAlex
W2975939935
Cited by
36
References
62
Citations by year
2025: 5 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 16 · 2020: 4
FWCI
2.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Health and Medical Research Council (APP1109286, APP11580823, APP1061779)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
endometrial cancer, GWAS risk loci, candidate target genes, enhancer-promoter interactions, chromatin looping, HiChIP, H3K27ac, HOXB2, BCL11A, protein-protein interaction network

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