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Orphan CpG Islands Identify Numerous Conserved Promoters in the Mammalian Genome


CpG islands (CGIs) are vertebrate genomic landmarks that encompass the promoters of most genes and often lack DNA methylation. Querying their apparent importance, the number of CGIs is reported to vary widely in different species and many do not co-localise with annotated promoters. We set out to quantify the number of CGIs in mouse and human genomes using CXXC Affinity Purification plus deep sequencing (CAP-seq). We also asked whether CGIs not associated with annotated transcripts share properties with those at known promoters. We found that, contrary to previous estimates, CGI abundance in humans and mice is very similar and many are at conserved locations relative to genes. In each species CpG density correlates positively with the degree of H3K4 trimethylation, supporting the hypothesis that these two properties are mechanistically interdependent. Approximately half of mammalian CGIs (>10,000) are “orphans” that are not associated with annotated promoters. Many orphan CGIs show evidence of transcriptional initiation and dynamic expression during development. Unlike CGIs at known promoters, orphan CGIs are frequently subject to DNA methylation during development, and this is accompanied by loss of their active promoter features. In colorectal tumors, however, orphan CGIs are not preferentially methylated, suggesting that cancer does not recapitulate a developmental program. Human and mouse genomes have similar numbers of CGIs, over half of which are remote from known promoters. Orphan CGIs nevertheless have the characteristics of functional promoters, though they are much more likely than promoter CGIs to become methylated during development and hence lose these properties. The data indicate that orphan CGIs correspond to previously undetected promoters whose transcriptional activity may play a functional role during development.


Vyšlo v časopise: Orphan CpG Islands Identify Numerous Conserved Promoters in the Mammalian Genome. PLoS Genet 6(9): e32767. doi:10.1371/journal.pgen.1001134
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001134

Souhrn

CpG islands (CGIs) are vertebrate genomic landmarks that encompass the promoters of most genes and often lack DNA methylation. Querying their apparent importance, the number of CGIs is reported to vary widely in different species and many do not co-localise with annotated promoters. We set out to quantify the number of CGIs in mouse and human genomes using CXXC Affinity Purification plus deep sequencing (CAP-seq). We also asked whether CGIs not associated with annotated transcripts share properties with those at known promoters. We found that, contrary to previous estimates, CGI abundance in humans and mice is very similar and many are at conserved locations relative to genes. In each species CpG density correlates positively with the degree of H3K4 trimethylation, supporting the hypothesis that these two properties are mechanistically interdependent. Approximately half of mammalian CGIs (>10,000) are “orphans” that are not associated with annotated promoters. Many orphan CGIs show evidence of transcriptional initiation and dynamic expression during development. Unlike CGIs at known promoters, orphan CGIs are frequently subject to DNA methylation during development, and this is accompanied by loss of their active promoter features. In colorectal tumors, however, orphan CGIs are not preferentially methylated, suggesting that cancer does not recapitulate a developmental program. Human and mouse genomes have similar numbers of CGIs, over half of which are remote from known promoters. Orphan CGIs nevertheless have the characteristics of functional promoters, though they are much more likely than promoter CGIs to become methylated during development and hence lose these properties. The data indicate that orphan CGIs correspond to previously undetected promoters whose transcriptional activity may play a functional role during development.


Zdroje

1. LanderES

LintonLM

BirrenB

NusbaumC

ZodyMC

2001 Initial sequencing and analysis of the human genome. Nature 409 860 921

2. VenterJC

AdamsMD

MyersEW

LiPW

MuralRJ

2001 The sequence of the human genome. Science 291 1304 1351

3. CrossSH

CharltonJA

NanX

BirdAP

1994 Purification of CpG islands using a methylated DNA binding column. Nat Genet 6 236 244

4. WeberM

HellmannI

StadlerMB

RamosL

PaaboS

2007 Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39 457 466

5. BirdAP

1980 DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 8 1499 1504

6. CoulondreC

MillerJH

FarabaughPJ

GilbertW

1978 Molecular basis of base substitution hotspots in Escherichia coli. Nature 274 775 780

7. IllingworthR

KerrA

DesousaD

JorgensenH

EllisP

2008 A novel CpG island set identifies tissue-specific methylation at developmental gene loci. PLoS Biol 6 e22

8. TaziJ

BirdA

1990 Alternative chromatin structure at CpG islands. Cell 60 909 920

9. BarskiA

CuddapahS

CuiK

RohTY

SchonesDE

2007 High-resolution profiling of histone methylations in the human genome. Cell 129 823 837

10. GuentherMG

LevineSS

BoyerLA

JaenischR

YoungRA

2007 A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130 77 88

11. MikkelsenTS

KuM

JaffeDB

IssacB

LiebermanE

2007 Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448 553 560

12. LeeJH

SkalnikDG

2005 CpG-binding protein (CXXC finger protein 1) is a component of the mammalian Set1 histone H3-Lys4 methyltransferase complex, the analogue of the yeast Set1/COMPASS complex. J Biol Chem 280 41725 41731

13. LeeJH

TateCM

YouJS

SkalnikDG

2007 Identification and characterization of the human Set1B histone H3-Lys4 methyltransferase complex. J Biol Chem 282 13419 13428

14. ThomsonJP

SkenePJ

SelfridgeJ

ClouaireT

GuyJ

2010 CpG islands influence chromatin structure via the CpG-binding protein Cfp1. Nature 464 1082 1086

15. Ramirez-CarrozziVR

BraasD

BhattDM

ChengCS

HongC

2009 A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138 114 128

16. AntequeraF

BirdA

1993 Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci U S A 90 11995 11999

17. WaterstonRH

Lindblad-TohK

BirneyE

RogersJ

AbrilJF

2002 Initial sequencing and comparative analysis of the mouse genome. Nature 420 520 562

18. CaoR

WangL

WangH

XiaL

Erdjument-BromageH

2002 Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298 1039 1043

19. CzerminB

MelfiR

McCabeD

SeitzV

ImhofA

2002 Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111 185 196

20. KuzmichevA

NishiokaK

Erdjument-BromageH

TempstP

ReinbergD

2002 Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev 16 2893 2905

21. MullerJ

HartCM

FrancisNJ

VargasML

SenguptaA

2002 Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111 197 208

22. TakaiD

JonesPA

2002 Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A 99 3740 3745

23. FouseSD

ShenY

PellegriniM

ColeS

MeissnerA

2008 Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell 2 160 169

24. MohnF

WeberM

RebhanM

RoloffTC

RichterJ

2008 Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Molecular Cell 30 755 766

25. Gardiner-GardenM

FrommerM

1994 Transcripts and CpG islands associated with the pro-opiomelanocortin gene and other neurally expressed genes. J Mol Endocrinol 12 365 382

26. KleinjanDA

SeawrightA

ChildsAJ

van HeyningenV

2004 Conserved elements in Pax6 intron 7 involved in (auto)regulation and alternative transcription. Dev Biol 265 462 477

27. MacleodD

AliRR

BirdA

1998 An alternative promoter in the mouse major histocompatibility complex class II I-Abeta gene: implications for the origin of CpG islands. Mol Cell Biol 18 4433 4443

28. KhalilAM

GuttmanM

HuarteM

GarberM

RajA

2009 Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proceedings of the National Academy of Sciences of the United States of America 106 11667 11672

29. GuttmanM

AmitI

GarberM

FrenchC

LinMF

2009 Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458 223 227

30. KimTH

BarreraLO

ZhengM

QuC

SingerMA

2005 A high-resolution map of active promoters in the human genome. Nature 436 876 880

31. HsuF

KentWJ

ClawsonH

KuhnRM

DiekhansM

2006 The UCSC Known Genes. Bioinformatics 22 1036 1046

32. CurwenV

EyrasE

AndrewsTD

ClarkeL

MonginE

2004 The Ensembl automatic gene annotation system. Genome Research 14 942 950

33. FaulknerGJ

KimuraY

DaubCO

WaniS

PlessyC

2009 The regulated retrotransposon transcriptome of mammalian cells. Nat Genet 41 563 571

34. CoreLJ

WaterfallJJ

LisJT

2008 Nascent RNA Sequencing Reveals Widespread Pausing and Divergent Initiation at Human Promoters. Science 322 1845 1848

35. RauchTA

WuX

ZhongX

RiggsAD

PfeiferGP

2009 A human B cell methylome at 100-base pair resolution. Proceedings of the National Academy of Sciences of the United States of America 106 671 678

36. SteinR

RazinA

CedarH

1982 In vitro methylation of the hamster adenine phosphoribosyltransferase gene inhibits its expression in mouse L cells. Proc Natl Acad Sci U S A 79 3418 3422

37. HansenRS

GartlerSM

1990 5-Azacytidine-induced reactivation of the human X chromosome-linked PGK1 gene is associated with a large region of cytosine demethylation in the 5′ CpG island. Proc Natl Acad Sci U S A 87 4174 4178

38. HuangTH

PerryMR

LauxDE

1999 Methylation profiling of CpG islands in human breast cancer cells. Hum Mol Genet 8 459 470

39. IrizarryRA

Ladd-AcostaC

WenB

WuZ

MontanoC

2009 The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nature Genetics 41 178 186

40. WeberM

DaviesJJ

WittigD

OakeleyEJ

HaaseM

2005 Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet

41. YanPS

EfferthT

ChenHL

LinJ

RodelF

2002 Use of CpG island microarrays to identify colorectal tumors with a high degree of concurrent methylation. Methods 27 162 169

42. KeshetI

SchlesingerY

FarkashS

RandE

HechtM

2006 Evidence for an instructive mechanism of de novo methylation in cancer cells. Nat Genet 38 149 153

43. OhmJE

McGarveyKM

YuX

ChengL

SchuebelKE

2007 A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39 237 242

44. SchlesingerY

StraussmanR

KeshetI

FarkashS

HechtM

2007 Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet 39 232 236

45. WidschwendterM

FieglH

EgleD

Mueller-HolznerE

SpizzoG

2007 Epigenetic stem cell signature in cancer. Nat Genet 39 157 158

46. KuM

KocheRP

RheinbayE

MendenhallEM

EndohM

2008 Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet 4 e1000242

47. CuadradoM

SacristanM

AntequeraF

2001 Species-specific organization of CpG island promoters at mammalian homologous genes. EMBO Rep 2 586 592

48. KanberD

BerulavaT

AmmerpohlO

MitterD

RichterJ

2009 The human retinoblastoma gene is imprinted. PLoS Genet 5 e1000790

49. RinnJL

KerteszM

WangJK

SquazzoSL

XuX

2007 Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129 1311 1323

50. SadoT

LiE

SasakiH

2002 Effect of TSIX disruption on XIST expression in male ES cells. Cytogenet Genome Res 99 115 118

51. SleutelsF

ZwartR

BarlowDP

2002 The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415 810 813

52. VireE

BrennerC

DeplusR

BlanchonL

FragaM

2006 The Polycomb group protein EZH2 directly controls DNA methylation. Nature 439 871 874

53. GuptaRA

ShahN

WangKC

KimJ

HorlingsHM

2010 Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464 1071 1076

54. HossainAM

RizkB

BehzadianA

ThorneycroftIH

1997 Modified guanidinium thiocyanate method for human sperm DNA isolation. Mol Hum Reprod 3 953 956

55. AflatoonianB

RubanL

ShamsuddinS

BakerD

AndrewsP

2010 Generation of Sheffield (Shef) human embryonic stem cell lines using a microdrop culture system. In Vitro Cell Dev Biol Anim

56. GuyJ

HendrichB

HolmesM

MartinJE

BirdA

2001 A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27 322 326

57. SkenePJ

IllingworthRS

WebbS

KerrARW

JamesKD

2010 Neuronal MeCP2 Is Expressed at Near Histone-Octamer Levels and Globally Alters the Chromatin State. Molecular Cell 37 457 468

58. SchmiedebergL

SkeneP

DeatonA

BirdA

2009 A temporal threshold for formaldehyde crosslinking and fixation. PLoS One 4 e4636

59. TaylorJ

SchenckI

BlankenbergD

NekrutenkoA

2007 Using galaxy to perform large-scale interactive data analyses. Curr Protoc Bioinformatics Chapter 10: Unit 10 15

60. NicolJW

HeltGA

BlanchardSGJr

RajaA

LoraineAE

2009 The Integrated Genome Browser: free software for distribution and exploration of genome-scale datasets. Bioinformatics 25 2730 2731

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