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Human Genetics

, Volume 134, Issue 11–12, pp 1183–1193 | Cite as

Scrutinizing the FTO locus: compelling evidence for a complex, long-range regulatory context

  • Mathias Rask-Andersen
  • Markus Sällman Almén
  • Helgi B. Schiöth
Original Investigation

Abstract

Single nucleotide polymorphisms (SNPs) within a genetic region including the first two introns of the gene encoding FTO have consistently been shown to be the strongest genetic factors influencing body mass index (BMI). However, this same also contains several regulatory DNA elements that affect the expression of IRX3 and IRX5, which respectively, are located approximately 500 kb and 1.2 Mbp downstream from the BMI-associated FTO locus. Through these affected regulatory elements, genetic variation at the FTO locus influences adipocyte development leading to decreased thermogenesis and increased lipid storage. These findings provide a genomic model for the functional implications of genetic variations at this locus, and also demonstrate the importance of accounting for chromatin–chromatin interactions when constructing hypotheses for the mechanisms of trait and disease-associated common genetic variants. Several consortia have generated genome-wide datasets describing different aspects of chromatin biology which can be utilized to predict functionality and propose biologically relevant descriptions of specific DNA regions. Here, we review some of the publically available data resources on genome function and organization that can be used to gain an overview of genetic regions of interest and to generate testable hypotheses for future studies. We use the BMI- and obesity-associated FTO locus as a subject as it poses an illustrative example on the value of these resources. We find that public databases strongly support long-range interactions between regulatory elements in the FTO locus with the IRXB cluster genes IRX3 and IRX5. Chromatin configuration capture data also support interactions across a large region stretching across from the RPGRIP1L gene, FTO and the IRXB gene cluster.

Keywords

Chromatin Interaction Promoter Interaction Encode Consortium Fantom Consortium Body Mass Regulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

MRA was supported by the Swedish Brain Research Foundation, The Lars Hierta Memorial Foundation and the Fredrik O Ingrid Thuring Foundation. Studies were supported by the Swedish Research Council. We would like to express our gratitude to Lyle Weimerslage, Ph.D. for assisting with the writing of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

439_2015_1599_MOESM1_ESM.pdf (1 mb)
Supplementary material 1 (PDF 1062 kb)

References

  1. Allende ML, Manzanares M, Tena JJ, Feijoo CG, Gomez-Skarmeta JL (2006) Cracking the genome’s second code: enhancer detection by combined phylogenetic footprinting and transgenic fish and frog embryos. Methods 39:212–219. doi: 10.1016/j.ymeth.2005.12.005 CrossRefPubMedGoogle Scholar
  2. Andersson R et al (2014) An atlas of active enhancers across human cell types and tissues. Nature 507:455–461. doi: 10.1038/nature12787 CrossRefPubMedGoogle Scholar
  3. Andralojc KM et al (2009) Ghrelin-producing epsilon cells in the developing and adult human pancreas. Diabetologia 52:486–493. doi: 10.1007/s00125-008-1238-y CrossRefPubMedGoogle Scholar
  4. Benedict C, Axelsson T, Soderberg S, Larsson A, Ingelsson E, Lind L, Schioth HB (2014) Brief communication: The fat mass and obesity-associated gene (FTO) is linked to higher plasma levels of the hunger hormone ghrelin and lower serum levels of the satiety hormone leptin in older adults. Diabetes. doi: 10.2337/db14-0470 Google Scholar
  5. Blanchette M et al (2004) Aligning multiple genomic sequences with the threaded blockset aligner. Genome Res 14:708–715. doi: 10.1101/gr.1933104 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Boissel S et al (2009) Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet 85:106–111. doi: 10.1016/j.ajhg.2009.06.002 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bulger M, Groudine M (2011) Functional and mechanistic diversity of distal transcription enhancers. Cell 144:327–339. doi: 10.1016/j.cell.2011.01.024 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Church C et al (2010) Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet 42:1086–1092. doi: 10.1038/ng.713 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Claussnitzer M et al (2015) FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. N Engl J Med. doi: 10.1056/NEJMoa1502214 PubMedGoogle Scholar
  10. Consortium F et al (2014) A promoter-level mammalian expression atlas. Nature 507:462–470. doi: 10.1038/nature13182 CrossRefGoogle Scholar
  11. Creyghton MP et al (2010) Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA 107:21931–21936. doi: 10.1073/pnas.1016071107 CrossRefPubMedPubMedCentralGoogle Scholar
  12. de la Calle-Mustienes E et al (2005) A functional survey of the enhancer activity of conserved non-coding sequences from vertebrate Iroquois cluster gene deserts. Genome Res 15:1061–1072. doi: 10.1101/gr.4004805 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Dekker J, Rippe K, Dekker M, Kleckner N (2002) Capturing chromosome conformation. Science 295:1306–1311. doi: 10.1126/science.1067799 CrossRefPubMedGoogle Scholar
  14. ENCODE Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489:57–74. doi: 10.1038/nature11247 CrossRefGoogle Scholar
  15. Ernst J, Kellis M (2012) ChromHMM: automating chromatin-state discovery and characterization. Nat Methods 9:215–216. doi: 10.1038/nmeth.1906 CrossRefPubMedPubMedCentralGoogle Scholar
  16. FANTOM Consortium RIKEN PMI and CLST (DGT) (2014) A promoter-level mammalian expression atlas. Nature 507:462–470. doi: 10.1038/nature13182 CrossRefGoogle Scholar
  17. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC, Ruther U (2009) Inactivation of the Fto gene protects from obesity. Nature 458:894–898. doi: 10.1038/nature07848 CrossRefPubMedGoogle Scholar
  18. Frayling TM et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894. doi: 10.1126/science.1141634 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Fredriksson R et al (2008) The obesity gene, FTO, is of ancient origin, up-regulated during food deprivation and expressed in neurons of feeding-related nuclei of the brain. Endocrinology 149:2062–2071. doi: 10.1210/en.2007-1457 CrossRefPubMedGoogle Scholar
  20. Fullwood MJ et al (2009) An oestrogen-receptor-alpha-bound human chromatin interactome. Nature 462:58–64. doi: 10.1038/nature08497 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Gerken T et al (2007) The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 318:1469–1472. doi: 10.1126/science.1151710 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Han Z et al (2010) Crystal structure of the FTO protein reveals basis for its substrate specificity. Nature 464:1205–1209. doi: 10.1038/nature08921 CrossRefPubMedGoogle Scholar
  23. Hon GC, Hawkins RD, Ren B (2009) Predictive chromatin signatures in the mammalian genome. Hum Mol Genet 18:R195–R201. doi: 10.1093/hmg/ddp409 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Houweling AC, Dildrop R, Peters T, Mummenhoff J, Moorman AF, Ruther U, Christoffels VM (2001) Gene and cluster-specific expression of the Iroquois family members during mouse development. Mech Dev 107:169–174CrossRefPubMedGoogle Scholar
  25. Jacobsson JA, Schioth HB, Fredriksson R (2012) The impact of intronic single nucleotide polymorphisms and ethnic diversity for studies on the obesity gene FTO. Obes Rev 13:1096–1109. doi: 10.1111/j.1467-789X.2012.01025.x CrossRefPubMedGoogle Scholar
  26. Jia G et al (2011) N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol 7:885–887. doi: 10.1038/nchembio.687 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Jowett JB et al (2010) Genetic variation at the FTO locus influences RBL2 gene expression. Diabetes 59:726–732. doi: 10.2337/db09-1277 CrossRefPubMedGoogle Scholar
  28. Karra E et al (2013) A link between FTO, ghrelin, and impaired brain food-cue responsivity. J Clin Investig 123:3539–3551. doi: 10.1172/JCI44403 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kellis M et al (2014) Defining functional DNA elements in the human genome. Proc Natl Acad Sci USA 111:6131–6138. doi: 10.1073/pnas.1318948111 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kundaje A et al (2015) Integrative analysis of 111 reference human epigenomes. Nature 518:317–330. doi: 10.1038/nature14248 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Li G et al (2012) Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148:84–98. doi: 10.1016/j.cell.2011.12.014 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Lieberman-Aiden E et al (2009) Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326:289–293. doi: 10.1126/science.1181369 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lindgren CM et al (2009) Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution. PLoS Genet 5:e1000508. doi: 10.1371/journal.pgen.1000508 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Lopez-Maury L, Marguerat S, Bahler J (2008) Tuning gene expression to changing environments: from rapid responses to evolutionary adaptation. Nat Rev Genet 9:583–593. doi: 10.1038/nrg2398 CrossRefPubMedGoogle Scholar
  35. Madsen MB, Birck MM, Fredholm M, Cirera S (2010) Expression studies of the obesity candidate gene FTO in pig. Anim Biotechnol 21:51–63. doi: 10.1080/10495390903381792 CrossRefPubMedGoogle Scholar
  36. Maurano MT et al (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337:1190–1195. doi: 10.1126/science.1222794 CrossRefPubMedPubMedCentralGoogle Scholar
  37. McTaggart JS, Lee S, Iberl M, Church C, Cox RD, Ashcroft FM (2011) FTO is expressed in neurones throughout the brain and its expression is unaltered by fasting. PLoS One 6:e27968. doi: 10.1371/journal.pone.0027968 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Montavon T, Duboule D (2013) Chromatin organization and global regulation of Hox gene clusters. Philos Trans R Soc Lond B Biol Sci 368:20120367. doi: 10.1098/rstb.2012.0367 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Olszewski PK et al (2009) Hypothalamic FTO is associated with the regulation of energy intake not feeding reward. BMC Neurosci 10:129. doi: 10.1186/1471-2202-10-129 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Ong CT, Corces VG (2011) Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet 12:283–293. doi: 10.1038/nrg2957 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Ong CT, Corces VG (2014) CTCF: an architectural protein bridging genome topology and function. Nat Rev Genet 15:234–246. doi: 10.1038/nrg3663 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Ovcharenko I, Loots GG, Nobrega MA, Hardison RC, Miller W, Stubbs L (2005) Evolution and functional classification of vertebrate gene deserts. Genome Res 15:137–145. doi: 10.1101/gr.3015505 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Park SJ, Komata M, Inoue F, Yamada K, Nakai K, Ohsugi M, Shirahige K (2013) Inferring the choreography of parental genomes during fertilization from ultralarge-scale whole-transcriptome analysis. Genes Dev 27:2736–2748. doi: 10.1101/gad.227926.113 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Peters T, Dildrop R, Ausmeier K, Ruther U (2000) Organization of mouse Iroquois homeobox genes in two clusters suggests a conserved regulation and function in vertebrate development. Genome Res 10:1453–1462CrossRefPubMedPubMedCentralGoogle Scholar
  45. Ragvin A et al (2010) Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. Proc Natl Acad Sci USA 107:775–780. doi: 10.1073/pnas.0911591107 CrossRefPubMedGoogle Scholar
  46. Rao SS et al (2014a) A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159:1665–1680. doi: 10.1016/j.cell.2014.11.021 CrossRefPubMedGoogle Scholar
  47. Rao SS, Lannutti JJ, Viapiano MS, Sarkar A, Winter JO (2014b) Toward 3D biomimetic models to understand the behavior of glioblastoma multiforme cells. Tissue Eng Part B Rev 20:314–327. doi: 10.1089/ten.TEB.2013.0227 CrossRefPubMedGoogle Scholar
  48. Siepel A et al (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15:1034–1050. doi: 10.1101/gr.3715005 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Siepel A, Pollard KS, Haussler D (2006) New methods for detecting lineage-specific selection. In: Proceedings of the 10th International Conference on Research in Computational Molecular Biology (RECOMB 2006), pp 190–205Google Scholar
  50. Smemo S et al (2014) Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507:371–375CrossRefPubMedPubMedCentralGoogle Scholar
  51. Speliotes EK et al (2010) Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 42:937–948. doi: 10.1038/ng.686 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Stratigopoulos G et al (2008) Regulation of Fto/Ftm gene expression in mice and humans. Am J Physiol Regul Integr Comp Physiol 294:R1185–R1196. doi: 10.1152/ajpregu.00839.2007 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Stratigopoulos G et al (2014) Hypomorphism for RPGRIP1L, a ciliary gene vicinal to the FTO locus, causes increased adiposity in mice. Cell Metab 19:767–779. doi: 10.1016/j.cmet.2014.04.009 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Tena JJ, Alonso ME, de la Calle-Mustienes E, Splinter E, de Laat W, Manzanares M, Gomez-Skarmeta JL (2011) An evolutionarily conserved three-dimensional structure in the vertebrate Irx clusters facilitates enhancer sharing and coregulation. Nat Commun 2:310. doi: 10.1038/ncomms1301 CrossRefPubMedGoogle Scholar
  55. Thurman RE et al (2012) The accessible chromatin landscape of the human genome. Nature 489:75–82. doi: 10.1038/nature11232 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Tsai MJ, O’Malley BW (1994) Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 63:451–486. doi: 10.1146/annurev.bi.63.070194.002315 CrossRefPubMedGoogle Scholar
  57. Yada T et al (2014) Ghrelin signalling in beta-cells regulates insulin secretion and blood glucose. Diabetes Obes Metab 16(Suppl 1):111–117. doi: 10.1111/dom.12344 CrossRefPubMedGoogle Scholar
  58. Zhang J et al (2012) ChIA-PET analysis of transcriptional chromatin interactions. Methods 58:289–299. doi: 10.1016/j.ymeth.2012.08.009 CrossRefPubMedGoogle Scholar
  59. Zhou X, Lowdon RF, Li D, Lawson HA, Madden PA, Costello JF, Wang T (2013) Exploring long-range genome interactions using the WashU Epigenome Browser. Nat Methods 10:375–376. doi: 10.1038/nmeth.2440 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Neuroscience, Division of Functional PharmacologyUppsala University, Biomedical Center (BMC)UppsalaSweden
  2. 2.Department of Medical Biochemistry and MicrobiologyUppsala University, BMCUppsalaSweden

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