GC-Rich Sequence Elements Recruit PRC2 in Mammalian ES Cells

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Polycomb proteins are epigenetic regulators that localize to developmental loci in the early embryo where they mediate lineage-specific gene repression. In Drosophila, these repressors are recruited to sequence elements by DNA binding proteins associated with Polycomb repressive complex 2 (PRC2). However, the sequences that recruit PRC2 in mammalian cells have remained obscure. To address this, we integrated a series of engineered bacterial artificial chromosomes into embryonic stem (ES) cells and examined their chromatin. We found that a 44 kb region corresponding to the Zfpm2 locus initiates de novo recruitment of PRC2. We then pinpointed a CpG island within this locus as both necessary and sufficient for PRC2 recruitment. Based on this causal demonstration and prior genomic analyses, we hypothesized that large GC-rich elements depleted of activating transcription factor motifs mediate PRC2 recruitment in mammals. We validated this model in two ways. First, we showed that a constitutively active CpG island is able to recruit PRC2 after excision of a cluster of activating motifs. Second, we showed that two 1 kb sequence intervals from the Escherichia coli genome with GC-contents comparable to a mammalian CpG island are both capable of recruiting PRC2 when integrated into the ES cell genome. Our findings demonstrate a causal role for GC-rich sequences in PRC2 recruitment and implicate a specific subset of CpG islands depleted of activating motifs as instrumental for the initial localization of this key regulator in mammalian genomes.

Vyšlo v časopise: GC-Rich Sequence Elements Recruit PRC2 in Mammalian ES Cells. PLoS Genet 6(12): e32767. doi:10.1371/journal.pgen.1001244
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001244

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Zdroje

1. SchuettengruberB

GanapathiM

LeblancB

PortosoM

JaschekR

2009 Functional anatomy of polycomb and trithorax chromatin landscapes in Drosophila embryos. PLoS Biol 7 e1000013 doi:10.1371/journal.pbio.1000013

2. SchwartzYB

PirrottaV

2007 Polycomb silencing mechanisms and the management of genomic programmes. Nat Rev Genet 8 9 22

3. BoyerLA

PlathK

ZeitlingerJ

BrambrinkT

MedeirosLA

2006 Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441 349 353

4. LeeTI

JennerRG

BoyerLA

GuentherMG

LevineSS

2006 Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125 301 313

5. KuM

KocheRP

RheinbayE

MendenhallEM

EndohM

2008 Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS Genet 4 e1000242 doi:10.1371/journal.pgen.1000242

6. AzuaraV

PerryP

SauerS

SpivakovM

JorgensenHF

2006 Chromatin signatures of pluripotent cell lines. Nat Cell Biol 8 532 538

7. BernsteinB

MikkelsenT

XieX

KamalK

HuebertD

2006 A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells. Cell 125 315 326

8. CaoR

WangL

WangH

XiaL

Erdjument-BromageH

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

9. 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

10. 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

11. HansenKH

BrackenAP

PasiniD

DietrichN

GehaniSS

2008 A model for transmission of the H3K27me3 epigenetic mark. Nat Cell Biol 10 1291 1300

12. MargueronR

JustinN

OhnoK

SharpeML

SonJ

2009 Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 461 762 767

13. RingroseL

ParoR

2007 Polycomb/Trithorax response elements and epigenetic memory of cell identity. Development 134 223 232

14. SimonJ

ChiangA

BenderW

ShimellMJ

O'ConnorM

1993 Elements of the Drosophila bithorax complex that mediate repression by Polycomb group products. Dev Biol 158 131 144

15. DejardinJ

RappaillesA

CuvierO

GrimaudC

DecovilleM

2005 Recruitment of Drosophila Polycomb group proteins to chromatin by DSP1. Nature 434 533 538

16. TolhuisB

de WitE

MuijrersI

TeunissenH

TalhoutW

2006 Genome-wide profiling of PRC1 and PRC2 Polycomb chromatin binding in Drosophila melanogaster. Nat Genet 38 694 699

17. WangL

BrownJL

CaoR

ZhangY

KassisJA

2004 Hierarchical recruitment of polycomb group silencing complexes. Mol Cell 14 637 646

18. SchwartzYB

KahnTG

NixDA

LiXY

BourgonR

2006 Genome-wide analysis of Polycomb targets in Drosophila melanogaster. Nat Genet 38 700 705

19. NegreN

HennetinJ

SunLV

LavrovS

BellisM

2006 Chromosomal distribution of PcG proteins during Drosophila development. PLoS Biol 4 e170 doi:10.1371/journal.pbio.0040170

20. AtchisonL

GhiasA

WilkinsonF

BoniniN

AtchisonML

2003 Transcription factor YY1 functions as a PcG protein in vivo. Embo J 22 1347 1358

21. KoCY

HsuHC

ShenMR

ChangWC

WangJM

2008 Epigenetic silencing of CCAAT/enhancer-binding protein delta activity by YY1/polycomb group/DNA methyltransferase complex. J Biol Chem 283 30919 30932

22. SuiG

Affar elB

ShiY

BrignoneC

WallNR

2004 Yin Yang 1 is a negative regulator of p53. Cell 117 859 872

23. YueR

KangJ

ZhaoC

HuW

TangY

2009 Beta-arrestin1 regulates zebrafish hematopoiesis through binding to YY1 and relieving polycomb group repression. Cell 139 535 546

24. LiuH

Schmidt-SupprianM

ShiY

HobeikaE

BartenevaN

2007 Yin Yang 1 is a critical regulator of B-cell development. Genes Dev 21 1179 1189

25. XiH

YuY

FuY

FoleyJ

HaleesA

2007 Analysis of overrepresented motifs in human core promoters reveals dual regulatory roles of YY1. Genome Res 17 798 806

26. KimJD

KangK

KimJ

2009 YY1's role in DNA methylation of Peg3 and Xist. Nucleic Acids Res 37 5656 5664

27. SingA

PannellD

KaraiskakisA

SturgeonK

DjabaliM

2009 A vertebrate Polycomb response element governs segmentation of the posterior hindbrain. Cell 138 885 897

28. WooCJ

KharchenkoPV

DaheronL

ParkPJ

KingstonRE

A region of the human HOXD cluster that confers polycomb-group responsiveness. Cell 140 99 110

29. BrackenAP

DietrichN

PasiniD

HansenKH

HelinK

2006 Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev 20 1123 1136

30. MohnF

WeberM

RebhanM

RoloffTC

RichterJ

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

31. TanayA

O'DonnellAH

DamelinM

BestorTH

2007 Hyperconserved CpG domains underlie Polycomb-binding sites. Proc Natl Acad Sci U S A 104 5521 5526

32. PasiniD

CloosPA

WalfridssonJ

OlssonL

BukowskiJP

JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature 464 306 310

33. LiG

MargueronR

KuM

ChambonP

BernsteinBE

Jarid2 and PRC2, partners in regulating gene expression. Genes Dev 24 368 380

34. PengJC

ValouevA

SwigutT

ZhangJ

ZhaoY

2009 Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell 139 1290 1302

35. ShenX

KimW

FujiwaraY

SimonMD

LiuY

2009 Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell 139 1303 1314

36. KimTG

KrausJC

ChenJ

LeeY

2003 JUMONJI, a critical factor for cardiac development, functions as a transcriptional repressor. J Biol Chem 278 42247 42255

37. TevosianSG

AlbrechtKH

CrispinoJD

FujiwaraY

EicherEM

2002 Gonadal differentiation, sex determination and normal Sry expression in mice require direct interaction between transcription partners GATA4 and FOG2. Development 129 4627 4634

38. ContiL

PollardSM

GorbaT

ReitanoE

ToselliM

2005 Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol 3 e283 doi:10.1371/journal.pbio.0030283

39. MikkelsenTS

KuM

JaffeDB

IssacB

LiebermanE

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

40. PouxS

McCabeD

PirrottaV

2001 Recruitment of components of Polycomb Group chromatin complexes in Drosophila. Development 128 75 85

41. SchmittS

PrestelM

ParoR

2005 Intergenic transcription through a polycomb group response element counteracts silencing. Genes Dev 19 697 708

42. 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

43. KimH

KangK

KimJ

2009 AEBP2 as a potential targeting protein for Polycomb Repression Complex PRC2. Nucleic Acids Res 37 2940 2950

44. CreyghtonMP

MarkoulakiS

LevineSS

HannaJ

LodatoMA

2008 H2AZ is enriched at polycomb complex target genes in ES cells and is necessary for lineage commitment. Cell 135 649 661

45. GoldbergAD

BanaszynskiLA

NohKM

LewisPW

ElsaesserSJ

Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140 678 691

46. TateCM

LeeJH

SkalnikDG

2009 CXXC Finger Protein 1 Contains Redundant Functional Domains That Support Embryonic Stem Cell Cytosine Methylation, Histone Methylation, and Differentiation. Mol Cell Biol

47. ZhaoJ

SunBK

ErwinJA

SongJJ

LeeJT

2008 Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 322 750 756

48. KanhereA

ViiriK

AraujoCC

RasaiyaahJ

BouwmanRD

Short RNAs are transcribed from repressed polycomb target genes and interact with polycomb repressive complex-2. Mol Cell 38 675 688

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. TsaiMC

ManorO

WanY

MosammaparastN

WangJK

Long noncoding RNA as modular scaffold of histone modification complexes. Science 329 689 693

51. LorenteM

PerezC

SanchezC

DonohoeM

ShiY

2006 Homeotic transformations of the axial skeleton of YY1 mutant mice and genetic interaction with the Polycomb group gene Ring1/Ring1A. Mech Dev 123 312 320

52. GarciaE

Marcos-GutierrezC

del Mar LorenteM

MorenoJC

VidalM

1999 RYBP, a new repressor protein that interacts with components of the mammalian Polycomb complex, and with the transcription factor YY1. Embo J 18 3404 3418

53. PollardSM

BenchouaA

LowellS

2006 Neural stem cells, neurons, and glia. Methods Enzymol 418 151 169

54. MrakRE

YasargilMG

MohapatraG

EarelJJr

LouisDN

2004 Atypical extraventricular neurocytoma with oligodendroglioma-like spread and an unusual pattern of chromosome 1p and 19q loss. Hum Pathol 35 1156 1159

55. MeissnerA

MikkelsenTS

GuH

WernigM

HannaJ

2008 Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454 766 770

56. BaileyTL

GribskovM

1998 Combining evidence using p-values: application to sequence homology searches. Bioinformatics 14 48 54

57. CloonanN

ForrestAR

KolleG