Genetic Landscape of Open Chromatin in Yeast

English version České info

Chromatin regulation underlies a variety of DNA metabolism processes, including transcription, recombination, repair, and replication. To perform a quantitative genetic analysis of chromatin accessibility, we obtained open chromatin profiles across 96 genetically different yeast strains by FAIRE (formaldehyde-assisted isolation of regulatory elements) assay followed by sequencing. While 5∼10% of open chromatin region (OCRs) were significantly affected by variations in their underlying DNA sequences, subtelomeric areas as well as gene-rich and gene-poor regions displayed high levels of sequence-independent variation. We performed quantitative trait loci (QTL) mapping using the FAIRE signal for each OCR as a quantitative trait. While individual OCRs were associated with a handful of specific genetic markers, gene expression levels were associated with many regulatory loci. We found multi-target trans-loci responsible for a very large number of OCRs, which seemed to reflect the widespread influence of certain chromatin regulators. Such regulatory hotspots were enriched for known regulatory functions, such as recombinational DNA repair, telomere replication, and general transcription control. The OCRs associated with these multi-target trans-loci coincided with recombination hotspots, telomeres, and gene-rich regions according to the function of the associated regulators. Our findings provide a global quantitative picture of the genetic architecture of chromatin regulation.

Vyšlo v časopise: Genetic Landscape of Open Chromatin in Yeast. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003229
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003229

Souhrn

Zdroje

1. BremRB, YvertG, ClintonR, KruglyakL (2002) Genetic dissection of transcriptional regulation in budding yeast. Science 296: 752–755.

2. SchadtEE, MonksSA, DrakeTA, LusisAJ, CheN, et al. (2003) Genetics of gene expression surveyed in maize, mouse and man. Nature 422: 297–302.

3. MorleyM, MolonyCM, WeberT, DevlinJL, EwensKG, et al. (2004) Genetic analysis of genome-wide variation in human gene expression. Nature 430: 743–747.

4. BremRB, StoreyJD, WhittleJ, KruglyakL (2005) Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436: 701–703.

5. CheungVG, SpielmanRS, EwensKG, WeberTM, MorleyM, et al. (2005) Mapping determinants of human gene expression by regional and genome-wide association. Nature 437: 1365–1369.

6. BremRB, KruglyakL (2005) The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc Natl Acad Sci 102: 1572–1577.

7. ChoiJK, KimYJ (2008) Epigenetic regulation and the variability of gene expression. Nat Genet 40: 141–147.

8. TiroshI, SigalN, BarkaiN (2010) Divergence of nucleosome positioning between two closely related yeast species: genetic basis and functional consequences. Mol Syst Biol 6: 365.

9. ZhengW, ZhaoH, ManceraE, SteinmetzLM, SnyderM (2010) Genetic analysis of variation in transcription factor binding in yeast. Nature 464: 1187–1191.

10. KasowskiM, GrubertF, HeffelfingerC, HariharanM, AsabereA, et al. (2010) Variation in transcription factor binding among humans. Science 328: 232–235.

11. McDaniellR, LeeB-K, SongL, LiuZ, BoyleAP, et al. (2010) Heritable individual-specific and allele-specific chromatin signatures in humans. Science 328: 235–239.

12. GiresiPG, KimJ, McDaniellRM, IyerVR, LiebJD (2007) FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regulatory elements from human chromatin. Genome Res 17: 877–885.

13. GaultonKJ, NammoT, PasqualiL, SimonJM, GiresiPG, et al. (2010) A map of open chromatin in human pancreatic islets. Nat Genet 42: 255–259.

14. SongL, ZhangZ, GrasfederLL, BoyleAP, GiresiPG, et al. (2011) Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. Genome Res 21: 1757–1767.

15. SmithAJP, HowardP, ShahS, ErikssonP, StenderS, et al. (2012) Use of allele-specific FAIRE to determine functional regulatory polymorphism using large-scale genotyping arrays. PLoS Genet 8: e1002908 doi:10.1371/journal.pgen.1002908.

16. DegnerJF, PaiAA, Pique-RegiR, VeyrierasJ-B, GaffneyDJ, et al. (2012) DNase I sensitivity QTLs are a major determinant of human expression variation. Nature 482: 390–394.

17. LeeS-I, Pe'erD, DudleyAM, ChurchGM, KollerD (2006) Identifying regulatory mechanisms using individual variation reveals key role for chromatin modification. Proc Natl Acad Sci 103: 14062–14067.

18. KleinHL (1997) RDH54, a RAD54 homologue in Saccharomyces cerevisiae,is required for mitotic diploid-specific recombination and repair and for meiosis. Genetics 147: 1533–1543.

19. PetukhovaG, SungP, KleinH (2000) Promotion of Rad51-dependent D-loop formation by yeast recombination factor Rdh54/Tid1. Genes & Dev 14: 2206–2215.

20. ShahPP, ZhengX, EpshteinA, CareyJN, BishopDK, et al. (2010) Swi2/Snf2-related translocases prevent accumulation of toxic Rad51 complexes during mitotic growth. Mol Cell 39: 862–872.

21. WuTC, LichtenM (1994) Meiosis-induced double-strand break sites determined by yeast chromatin structure. Science 263: 515–518.

22. GertonJL, DeRisiJ, ShroffR, LichtenM, BrownPO, et al. (2000) Global mapping of meiotic recombination hotspots and coldspots in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci 97: 11383–11390.

23. NugentCI, HughesTR, LueNF, LundbladV (1996) Cdc13p: a single-strand telomeric DNA-binding protein with a dual role in yeast telomere maintenance. Science 274: 249–252.

24. EvansSK, LundbladV (1999) Est1 and Cdc13 as comediators of telomerase access. Science 286: 117–120.

25. LustigAJ (2001) Cdc13 subcomplexes regulate multiple telomere functions. Nat Struct Biol 8: 297–299.

26. YvertG, BremRB, WhittleJ, AkeyJM, FossE, et al. (2003) Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nat Genet 35: 57–64.

27. BoyleAP, GuinneyJ, CrawfordGE, FureyTS (2008) F-Seq: a feature density estimator for high-throughput sequence tags. Bioinformatics 24: 2537–2538.

28. QuinlanAR, HallIM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26: 841–842.

29. ChoiJK (2010) Contrasting chromatin organization of CpG islands and exons in the human genome. Genome Biol 11: R70.

30. BenjaminiY, HochbergY (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Statist Soc Ser B 57: 289–300.

31. MacIsaacKD, WangT, GordonDB, GiffordDK, StormoGD, et al. (2006) An improved map of conserved regulatory sites for Saccharomyces cerevisiae. BMC Bioinformatics 7: 113.

32. HarbisonCT, GordonDB, LeeTI, RinaldiNJ, MacisaacKD, et al. (2004) Transcriptional regulatory code of a eukaryotic genome. Nature 431: 99–104.

33. BadisG, ChanET, BakelHv, Pena-CastilloL, TilloD, et al. (2008) A Library of Yeast Transcription Factor Motifs Reveals a Widespread Function for Rsc3 in Targeting Nucleosome Exclusion at Promoters. Mol Cell 32: 878–887.

34. HeinzS, BennerC, SpannN, BertolinoE, LinYC, et al. (2010) Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities. Mol Cell 38: 576–589.