Skip to main content
SpringerLink
Log in

Epigenetics and Control of RNAs

  • Protocol
  • First Online:
Systems Genetics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1488))

Abstract

Histone modifications are epigenetic marks that fundamentally impact the regulation of gene expression. Integrating histone modification information in the analysis of gene expression traits (eQTL mapping) has been shown to significantly enhance the prediction of eQTLs. In this chapter, we describe (1) how to perform quantitative trait locus (QTL) analysis using histone modification levels as traits and (2) how to integrate these data with information on RNA expression for the elucidation of the epigenetic control of transcript levels. We will provide a comprehensive introduction into the topic, describe in detail how ChIP-seq data are analyzed and elaborate on how to integrate ChIP-seq and RNA-seq data from a segregating disease animal model for the identification of the epigenetic control of RNA expression.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K (2007) High-resolution profiling of histone methylations in the human genome. Cell 129(4):823–837. doi:10.1016/j.cell.2007.05.009

    Article  CAS  PubMed  Google Scholar 

  2. Mikkelsen TS, Ku M, Jaffe DB, Issac B, Lieberman E, Giannoukos G, Alvarez P, Brockman W, Kim TK, Koche RP, Lee W, Mendenhall E, O’Donovan A, Presser A, Russ C, Xie X, Meissner A, Wernig M, Jaenisch R, Nusbaum C, Lander ES, Bernstein BE (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448(7153):553–560. doi:10.1038/nature06008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ernst J, Kheradpour P, Mikkelsen TS, Shoresh N, Ward LD, Epstein CB, Zhang X, Wang L, Issner R, Coyne M, Ku M, Durham T, Kellis M, Bernstein BE (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473(7345):43–49. doi:10.1038/nature09906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Pravenec M, Churchill PC, Churchill MC, Viklicky O, Kazdova L, Aitman TJ, Petretto E, Hubner N, Wallace CA, Zimdahl H, Zidek V, Landa V, Dunbar J, Bidani A, Griffin K, Qi N, Maxova M, Kren V, Mlejnek P, Wang J, Kurtz TW (2008) Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension. Nat Genet 40(8):952–954. doi:10.1038/ng.164

    Article  CAS  PubMed  Google Scholar 

  5. Hubner N, Wallace CA, Zimdahl H, Petretto E, Schulz H, Maciver F, Mueller M, Hummel O, Monti J, Zidek V, Musilova A, Kren V, Causton H, Game L, Born G, Schmidt S, Muller A, Cook SA, Kurtz TW, Whittaker J, Pravenec M, Aitman TJ (2005) Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nat Genet 37(3):243–253. doi:10.1038/ng1522

    Article  CAS  PubMed  Google Scholar 

  6. Printz MP, Jirout M, Jaworski R, Alemayehu A, Kren V (2003) Genetic Models in Applied Physiology. HXB/BXH rat recombinant inbred strain platform: a newly enhanced tool for cardiovascular, behavioral, and developmental genetics and genomics. J Appl Physiol 94(6):2510–2522. doi:10.1152/japplphysiol.00064.2003

    Article  CAS  PubMed  Google Scholar 

  7. Simonis M, Atanur SS, Linsen S, Guryev V, Ruzius FP, Game L, Lansu N, de Bruijn E, van Heesch S, Jones SJ, Pravenec M, Aitman TJ, Cuppen E (2012) Genetic basis of transcriptome differences between the founder strains of the rat HXB/BXH recombinant inbred panel. Genome Biol 13(4):r31. doi:10.1186/gb-2012-13-4-r31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kasowski M, Kyriazopoulou-Panagiotopoulou S, Grubert F, Zaugg JB, Kundaje A, Liu Y, Boyle AP, Zhang QC, Zakharia F, Spacek DV, Li J, Xie D, Olarerin-George A, Steinmetz LM, Hogenesch JB, Kellis M, Batzoglou S, Snyder M (2013) Extensive variation in chromatin states across humans. Science 342(6159):750–752. doi:10.1126/science.1242510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. McVicker G, van de Geijn B, Degner JF, Cain CE, Banovich NE, Raj A, Lewellen N, Myrthil M, Gilad Y, Pritchard JK (2013) Identification of genetic variants that affect histone modifications in human cells. Science 342(6159):747–749. doi:10.1126/science.1242429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Rintisch C, Heinig M, Bauerfeind A, Schafer S, Mieth C, Patone G, Hummel O, Chen W, Cook S, Cuppen E, Colome-Tatche M, Johannes F, Jansen RC, Neil H, Werner M, Pravenec M, Vingron M, Hubner N (2014) Natural variation of histone modification and its impact on gene expression in the rat genome. Genome Res 24(6):942–953. doi:10.1101/gr.169029.113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Heinz S, Romanoski CE, Benner C, Allison KA, Kaikkonen MU, Orozco LD, Glass CK (2013) Effect of natural genetic variation on enhancer selection and function. Nature 503(7477):487–492. doi:10.1038/nature12615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kilpinen H, Waszak SM, Gschwind AR, Raghav SK, Witwicki RM, Orioli A, Migliavacca E, Wiederkehr M, Gutierrez-Arcelus M, Panousis NI, Yurovsky A, Lappalainen T, Romano-Palumbo L, Planchon A, Bielser D, Bryois J, Padioleau I, Udin G, Thurnheer S, Hacker D, Core LJ, Lis JT, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2013) Coordinated effects of sequence variation on DNA binding, chromatin structure, and transcription. Science 342(6159):744–747. doi:10.1126/science.1242463

    Article  CAS  PubMed  Google Scholar 

  13. Heinig M, Colome-Tatche M, Taudt A, Rintisch C, Schafer S, Pravenec M, Hubner N, Vingron M, Johannes F (2015) histoneHMM: differential analysis of histone modifications with broad genomic footprints. BMC Bioinformatics 16:60. doi:10.1186/s12859-015-0491-6

    Article  PubMed  PubMed Central  Google Scholar 

  14. Parkinson H, Kapushesky M, Shojatalab M, Abeygunawardena N, Coulson R, Farne A, Holloway E, Kolesnykov N, Lilja P, Lukk M, Mani R, Rayner T, Sharma A, William E, Sarkans U, Brazma A (2007) ArrayExpress--a public database of microarray experiments and gene expression profiles. Nucleic Acids Res 35(Database issue):D747–D750. doi:10.1093/nar/gkl995

    Article  CAS  PubMed  Google Scholar 

  15. Leinonen R, Akhtar R, Birney E, Bower L, Cerdeno-Tarraga A, Cheng Y, Cleland I, Faruque N, Goodgame N, Gibson R, Hoad G, Jang M, Pakseresht N, Plaister S, Radhakrishnan R, Reddy K, Sobhany S, Ten Hoopen P, Vaughan R, Zalunin V, Cochrane G (2011) The European Nucleotide Archive. Nucleic Acids Res 39(Database issue):D28–D31. doi:10.1093/nar/gkq967

    Article  CAS  PubMed  Google Scholar 

  16. Andrews S (2010) FastQC: a quality control tool for high throughput sequence data

    Google Scholar 

  17. Langmead B, Salzberg SL (2012) Fast gapped-read alignment with Bowtie 2. Nat Methods 9(4):357–359. doi:10.1038/nmeth.1923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R, Genome Project Data Processing Subgroup (2009) The sequence alignment/map format and SAMtools. Bioinformatics 25(16):2078–2079. doi:10.1093/bioinformatics/btp352

    Article  PubMed  PubMed Central  Google Scholar 

  19. Marinov GK, Kundaje A, Park PJ, Wold BJ (2014) Large-scale quality analysis of published ChIP-seq data. G3 (Bethesda) 4(2):209–223. doi:10.1534/g3.113.008680

    Article  Google Scholar 

  20. Heinig M (2015) Toolset for preprocessing sequencing based trais for QTL analysis. https://github.com/matthiasheinig/seqQTL

  21. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM, Brown M, Li W, Liu XS (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9(9):R137. doi:10.1186/gb-2008-9-9-r137

    Article  PubMed  PubMed Central  Google Scholar 

  22. Consortium GT (2015) Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348(6235):648–660. doi:10.1126/science.1262110

    Article  Google Scholar 

  23. Shabalin AA (2012) Matrix eQTL: ultra fast eQTL analysis via large matrix operations. Bioinformatics 28(10):1353–1358. doi:10.1093/bioinformatics/bts163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Heinig M (2015) Toolset to perform eQTL analysis on HPC systems. https://github.com/matthiasheinig/eQTLpipeline

  25. Bischl B (2015) BatchJobs and BatchExperiments: abstraction mechanisms for using R in batch environments. http://www.jstatsoft.org/article/view/v064i11

  26. Dowle M, Srinivasan A, Short T, Lianoglou S with contributions from Saporta R, Antonyan E (2015) Extension of Data.frame. https://github.com/Rdatatable/data.table/wiki

  27. Waszak SM, Delaneau O, Gschwind AR, Kilpinen H, Raghav SK, Witwicki RM, Orioli A, Wiederkehr M, Panousis NI, Yurovsky A, Romano-Palumbo L, Planchon A, Bielser D, Padioleau I, Udin G, Thurnheer S, Hacker D, Hernandez N, Reymond A, Deplancke B, Dermitzakis ET (2015) Population variation and genetic control of modular chromatin architecture in humans. Cell 162(5):1039–1050. doi:10.1016/j.cell.2015.08.001

    Article  CAS  PubMed  Google Scholar 

  28. Schadt EE, Lamb J, Yang X, Zhu J, Edwards S, Guhathakurta D, Sieberts SK, Monks S, Reitman M, Zhang C, Lum PY, Leonardson A, Thieringer R, Metzger JM, Yang L, Castle J, Zhu H, Kash SF, Drake TA, Sachs A, Lusis AJ (2005) An integrative genomics approach to infer causal associations between gene expression and disease. Nat Genet 37(7):710–717. doi:10.1038/ng1589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Encode Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414):57–74. doi:10.1038/nature11247

    Article  Google Scholar 

  30. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP (2011) Integrative genomics viewer. Nat Biotechnol 29(1):24–26. doi:10.1038/nbt.1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Skinner ME, Uzilov AV, Stein LD, Mungall CJ, Holmes IH (2009) JBrowse: a next-generation genome browser. Genome Res 19(9):1630–1638. doi:10.1101/gr.094607.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mott R, Talbot CJ, Turri MG, Collins AC, Flint J (2000) A method for fine mapping quantitative trait loci in outbred animal stocks. Proc Natl Acad Sci U S A 97(23):12649–12654. doi:10.1073/pnas.230304397

    Article  PubMed  PubMed Central  Google Scholar 

  33. Valdar W, Solberg LC, Gauguier D, Burnett S, Klenerman P, Cookson WO, Taylor MS, Rawlins JN, Mott R, Flint J (2006) Genome-wide genetic association of complex traits in heterogeneous stock mice. Nat Genet 38(8):879–887. doi:10.1038/ng1840

    Article  CAS  PubMed  Google Scholar 

  34. Rat Genome Sequencing and Mapping Consortium, Baud A, Hermsen R, Guryev V, Stridh P, Graham D, McBride MW, Foroud T, Calderari S, Diez M, Ockinger J, Beyeen AD, Gillett A, Abdelmagid N, Guerreiro-Cacais AO, Jagodic M, Tuncel J, Norin U, Beattie E, Huynh N, Miller WH, Koller DL, Alam I, Falak S, Osborne-Pellegrin M, Martinez-Membrives E, Canete T, Blazquez G, Vicens-Costa E, Mont-Cardona C, Diaz-Moran S, Tobena A, Hummel O, Zelenika D, Saar K, Patone G, Bauerfeind A, Bihoreau MT, Heinig M, Lee YA, Rintisch C, Schulz H, Wheeler DA, Worley KC, Muzny DM, Gibbs RA, Lathrop M, Lansu N, Toonen P, Ruzius FP, de Bruijn E, Hauser H, Adams DJ, Keane T, Atanur SS, Aitman TJ, Flicek P, Malinauskas T, Jones EY, Ekman D, Lopez-Aumatell R, Dominiczak AF, Johannesson M, Holmdahl R, Olsson T, Gauguier D, Hubner N, Fernandez-Teruel A, Cuppen E, Mott R, Flint J (2013) Combined sequence-based and genetic mapping analysis of complex traits in outbred rats. Nat Genet 45(7):767–775. doi:10.1038/ng.2644

    Article  Google Scholar 

  35. Johannesson M, Lopez-Aumatell R, Stridh P, Diez M, Tuncel J, Blazquez G, Martinez-Membrives E, Canete T, Vicens-Costa E, Graham D, Copley RR, Hernandez-Pliego P, Beyeen AD, Ockinger J, Fernandez-Santamaria C, Gulko PS, Brenner M, Tobena A, Guitart-Masip M, Gimenez-Llort L, Dominiczak A, Holmdahl R, Gauguier D, Olsson T, Mott R, Valdar W, Redei EE, Fernandez-Teruel A, Flint J (2009) A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock. Genome Res 19(1):150–158. doi:10.1101/gr.081497.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tolstorukov MY, Kharchenko PV, Goldman JA, Kingston RE, Park PJ (2009) Comparative analysis of H2A.Z nucleosome organization in the human and yeast genomes. Genome Res 19(6):967–977. doi:10.1101/gr.084830.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tang F, Barbacioru C, Wang Y, Nordman E, Lee C, Xu N, Wang X, Bodeau J, Tuch BB, Siddiqui A, Lao K, Surani MA (2009) mRNA-Seq whole-transcriptome analysis of a single cell. Nat Methods 6(5):377–382. doi:10.1038/nmeth.1315

    Article  CAS  PubMed  Google Scholar 

  38. Rotem A, Ram O, Shoresh N, Sperling RA, Goren A, Weitz DA, Bernstein BE (2015) Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat Biotechnol 33:1165–1172. doi:10.1038/nbt.3383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by funding from the European Union EURATRANS award (HEALTH-F4-2010-241504 to N.H.), the Helmholtz Alliance ICEMED, the Deutsche Forschungsgemeinschaft (Forschergruppe 1054, HU 1522/1-1) to N.H, and an EMBO Long-Term Fellowship (ALTF 186-2015) and Marie Curie Actions (LTFCOFUND2013, GA-2013-609409) to SvH.

Author information

Author notes

    Authors and Affiliations

    1. Max-Delbrück-Center for Molecular Medicine (MDC), 13125, Berlin, Germany

      Henrike Maatz, Sebastiaan van Heesch, Franziska Kreuchwig, Allison Faber, Eleonora Adami & Norbert Hubner

    2. Helmholtz Zentrum München, Institute of Computational Biology (ICB), Neuherberg, 85764, Germany

      Matthias Heinig

    3. DZHK (German Centre for Cardiovascular Research), Partner Site, 13347, Berlin, Germany

      Norbert Hubner

    4. Charité-Universitätsmedizin, 10117, Berlin, Germany

      Norbert Hubner

    Authors
    1. Henrike Maatz
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Sebastiaan van Heesch
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Franziska Kreuchwig
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Allison Faber
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Eleonora Adami
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Norbert Hubner
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Matthias Heinig
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Norbert Hubner or Matthias Heinig .

    Editor information

    Editors and Affiliations

    1. Department of Infection Genetics, Helmholtz Centre for Infection Research & University of Veterinary Medicine Hannover, Braunschweig, Niedersachsen, Germany

      Klaus Schughart

    2. Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA

      Robert W. Williams

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2017 Springer Science+Business Media New York

    About this protocol

    Cite this protocol

    Maatz, H. et al. (2017). Epigenetics and Control of RNAs. In: Schughart, K., Williams, R. (eds) Systems Genetics. Methods in Molecular Biology, vol 1488. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6427-7_9

    Download citation

    • DOI: https://doi.org/10.1007/978-1-4939-6427-7_9

    • Published:

    • Publisher Name: Humana Press, New York, NY

    • Print ISBN: 978-1-4939-6425-3

    • Online ISBN: 978-1-4939-6427-7

    • eBook Packages: Springer Protocols

    Publish with us

    Policies and ethics

    Search

    Navigation