Tissue-Specific RNA Expression Marks Distant-Acting Developmental Enhancers

English version České info

Up to 80% of mammalian genomes are actively transcribed, producing large numbers of non-coding RNAs without known functions. One particularly exciting category of such non-coding transcripts are the recently discovered enhancer RNAs (eRNAs) transcribed from distant-acting enhancer elements. Studies in cell-based paradigms suggest a functional requirement for such eRNA in enhancer-mediated gene regulation. In this study, we explored the in vivo expression dynamics of tissue-specific non-coding RNAs in embryonic mouse tissues via in-depth transcriptome profiling. Our results suggest that enhancers may be a predominant function associated with differentially expressed non-coding loci across developing tissues, and that differential eRNA expression signatures from total RNA-Seq can be used to identify uncharacterized tissue-specific in vivo enhancers independent of known epigenomic marks. Our results highlight the widespread and potentially important role of eRNAs in orchestrating gene expression and the necessity for functional studies in interpreting genome-wide enhancer predictions.

Vyšlo v časopise: Tissue-Specific RNA Expression Marks Distant-Acting Developmental Enhancers. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004610
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004610

Souhrn

Zdroje

1. OngCT, CorcesVG (2011) Enhancer function: new insights into the regulation of tissue-specific gene expression. Nat Rev Genet 12: 283–293.

2. ViselA, RubinEM, PennacchioLA (2009) Genomic views of distant-acting enhancers. Nature 461: 199–205.

3. BueckerC, WysockaJ (2012) Enhancers as information integration hubs in development: lessons from genomics. Trends Genet 28: 276–284.

4. FurnissD, LetticeLA, TaylorIB, CritchleyPS, GieleH, et al. (2008) A variant in the sonic hedgehog regulatory sequence (ZRS) is associated with triphalangeal thumb and deregulates expression in the developing limb. Hum Mol Genet 17: 2417–2423.

5. LetticeLA, HeaneySJ, PurdieLA, LiL, de BeerP, et al. (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 12: 1725–1735.

6. MasuyaH, SezutsuH, SakurabaY, SagaiT, HosoyaM, et al. (2007) A series of ENU-induced single-base substitutions in a long-range cis-element altering Sonic hedgehog expression in the developing mouse limb bud. Genomics 89: 207–214.

7. SagaiT, HosoyaM, MizushinaY, TamuraM, ShiroishiT (2005) Elimination of a long-range cis-regulatory module causes complete loss of limb-specific Shh expression and truncation of the mouse limb. Development 132: 797–803.

8. ViselA, ZhuY, MayD, AfzalV, GongE, et al. (2010) Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464: 409–412.

9. AttanasioC, NordAS, ZhuY, BlowMJ, LiZ, et al. (2013) Fine tuning of craniofacial morphology by distant-acting enhancers. Science 342: 1241006.

10. AbecasisGR, AltshulerD, AutonA, BrooksLD, DurbinRM, et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.

11. CotneyJ, LengJ, OhS, DeMareLE, ReillySK, et al. (2012) Chromatin state signatures associated with tissue-specific gene expression and enhancer activity in the embryonic limb. Genome Res 22: 1069–1080.

12. HeintzmanND, HonGC, HawkinsRD, KheradpourP, StarkA, et al. (2009) Histone modifications at human enhancers reflect global cell-type-specific gene expression. Nature 459: 108–112.

13. ErnstJ, KheradpourP, MikkelsenTS, ShoreshN, WardLD, et al. (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473: 43–49.

14. MastonGA, LandtSG, SnyderM, GreenMR (2012) Characterization of Enhancer Function from Genome-Wide Analyses. Annu Rev Genomics Hum Genet

15. NoonanJP, McCallionAS (2010) Genomics of long-range regulatory elements. Annu Rev Genomics Hum Genet 11: 1–23.

16. ParkPJ (2009) ChIP-seq: advantages and challenges of a maturing technology. Nat Rev Genet 10: 669–680.

17. WangD, Garcia-BassetsI, BennerC, LiW, SuX, et al. (2011) Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474: 390–394.

18. KimTK, HembergM, GrayJM, CostaAM, BearDM, et al. (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465: 182–187.

19. ZhuY, SunL, ChenZ, WhitakerJW, WangT, et al. (2013) Predicting enhancer transcription and activity from chromatin modifications. Nucleic Acids Res

20. HahN, MurakamiS, NagariA, DankoCG, KrausWL (2013) Enhancer transcripts mark active estrogen receptor binding sites. Genome Res 23: 1210–1223.

21. AnderssonR, GebhardC, Miguel-EscaladaI, HoofI, BornholdtJ, et al. (2014) An atlas of active enhancers across human cell types and tissues. Nature 507: 455–461.

22. LiW, NotaniD, MaQ, TanasaB, NunezE, et al. (2013) Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498: 516–520.

23. MeloCA, DrostJ, WijchersPJ, van de WerkenH, de WitE, et al. (2013) eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell 49: 524–535.

24. ViselA, MinovitskyS, DubchakI, PennacchioLA (2007) VISTA Enhancer Browser–a database of tissue-specific human enhancers. Nucleic Acids Res 35: D88–92.

25. PennacchioLA, AhituvN, MosesAM, PrabhakarS, NobregaMA, et al. (2006) In vivo enhancer analysis of human conserved non-coding sequences. Nature 444: 499–502.

26. BlowMJ, McCulleyDJ, LiZ, ZhangT, AkiyamaJA, et al. (2010) ChIP-Seq identification of weakly conserved heart enhancers. Nat Genet 42: 806–810.

27. ViselA, BlowMJ, LiZ, ZhangT, AkiyamaJA, et al. (2009) ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457: 854–858.

28. MayD, BlowMJ, KaplanT, McCulleyDJ, JensenBC, et al. (2011) Large-scale discovery of enhancers from human heart tissue. Nat Genet

29. NordAS, BlowMJ, AttanasioC, AkiyamaJA, HoltA, et al. (2013) Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell 155: 1521–1531.

30. A promoter-level mammalian expression atlas. Nature 507: 462–470.

31. ShenY, YueF, McClearyDF, YeZ, EdsallL, et al. (2012) A map of the cis-regulatory sequences in the mouse genome. Nature 488: 116–120.

32. LiuY, LiuXS, WeiL, AltmanRB, BatzoglouS (2004) Eukaryotic regulatory element conservation analysis and identification using comparative genomics. Genome Res 14: 451–458.

33. ViselA, PrabhakarS, AkiyamaJA, ShoukryM, LewisKD, et al. (2008) Ultraconservation identifies a small subset of extremely constrained developmental enhancers. Nat Genet 40: 158–160.

34. CarninciP, YasudaJ, HayashizakiY (2008) Multifaceted mammalian transcriptome. Curr Opin Cell Biol 20: 274–280.

35. CarninciP, KasukawaT, KatayamaS, GoughJ, FrithMC, et al. (2005) The transcriptional landscape of the mammalian genome. Science 309: 1559–1563.

36. HangauerMJ, VaughnIW, McManusMT (2013) Pervasive transcription of the human genome produces thousands of previously unidentified long intergenic noncoding RNAs. PLoS Genet 9: e1003569.

37. DjebaliS, DavisCA, MerkelA, DobinA, LassmannT, et al. (2012) Landscape of transcription in human cells. Nature 489: 101–108.

38. KaikkonenMU, SpannNJ, HeinzS, RomanoskiCE, AllisonKA, et al. (2013) Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription. Mol Cell 51: 310–325.

39. NatoliG, AndrauJC (2012) Noncoding transcription at enhancers: general principles and functional models. Annu Rev Genet 46: 1–19.

40. LamMT, ChoH, LeschHP, GosselinD, HeinzS, et al. (2013) Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. Nature 498: 511–515.

41. LangmeadB, SalzbergSL (2012) Fast gapped-read alignment with Bowtie 2. Nat Methods 9: 357–359.

42. NixDA, CourdySJ, BoucherKM (2008) Empirical methods for controlling false positives and estimating confidence in ChIP-Seq peaks. BMC Bioinformatics 9: 523.

43. KalAJ, van ZonneveldAJ, BenesV, van den BergM, KoerkampMG, et al. (1999) Dynamics of gene expression revealed by comparison of serial analysis of gene expression transcript profiles from yeast grown on two different carbon sources. Mol Biol Cell 10: 1859–1872.

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

45. AttanasioC, NordAS, ZhuY, BlowMJ, BiddieSC, et al. (2014) Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis. Genome Res

46. ZhangY, LiuT, MeyerCA, EeckhouteJ, JohnsonDS, et al. (2008) Model-based analysis of ChIP-Seq (MACS). Genome Biol 9: R137.

47. SiepelA, BejeranoG, PedersenJS, HinrichsAS, HouM, et al. (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res 15: 1034–1050.

48. McLeanCY, BristorD, HillerM, ClarkeSL, SchaarBT, et al. (2010) GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol 28: 495–501.

49. 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.

50. LivakKJ, SchmittgenTD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402–408.

51. KotharyR, ClapoffS, BrownA, CampbellR, PetersonA, et al. (1988) A transgene containing lacZ inserted into the dystonia locus is expressed in neural tube. Nature 335: 435–437.

52. NobregaMA, OvcharenkoI, AfzalV, RubinEM (2003) Scanning human gene deserts for long-range enhancers. Science 302: 413.