Home LiteratureArticle Details
PMID: 22056776 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't

An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment.

The EMBO journal ·Vol. 31 ·No. 2 ·2012-01-18 ·Pages 317-29

Lynch MD, Smith AJ, De Gobbi M, Flenley M, Hughes JR, Vernimmen D, Ayyub H, Sharpe JA, Sloane-Stanley JA, Sutherland L, Meek S, Burdon T, Gibbons RJ, Garrick D, Higgs DR

Abstract

The role of DNA sequence in determining chromatin state is incompletely understood. We have previously demonstrated that large chromosomal segments from human cells recapitulate their native chromatin state in mouse cells, but the relative contribution of local sequences versus their genomic context remains unknown. In this study, we compare orthologous chromosomal regions for which the human locus establishes prominent sites of Polycomb complex recruitment in pluripotent stem cells, whereas the corresponding mouse locus does not. Using recombination-mediated cassette exchange at the mouse locus, we establish the primacy of local sequences in the encoding of chromatin state. We show that the signal for chromatin bivalency is redundantly encoded across a bivalent domain and that this reflects competition between Polycomb complex recruitment and transcriptional activation. Furthermore, our results suggest that a high density of unmethylated CpG dinucleotides is sufficient for vertebrate Polycomb recruitment. This model is supported by analysis of DNA methyltransferase-deficient embryonic stem cells.

MeSH Terms
Animals Cells, Cultured/metabolism Chromatin/genetics Chromosome Mapping Chromosomes, Human, Pair 16 CpG Islands/physiology DNA Methylation DNA, Recombinant/genetics Embryonic Stem Cells/metabolism Gene Expression Regulation/genetics Humans Mice Mice, Transgenic Pluripotent Stem Cells/metabolism Polycomb-Group Proteins Recombination, Genetic Regulatory Sequences, Nucleic Acid Repressor Proteins/metabolism Species Specificity Transcription, Genetic alpha-Globins/genetics
Chemicals
Chromatin DNA, Recombinant Polycomb-Group Proteins Repressor Proteins alpha-Globins
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Lynch Magnus D
MRC Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
Smith Andrew J H
De Gobbi Marco
Flenley Maria
Hughes Jim R
Vernimmen Douglas
Ayyub Helena
Sharpe Jacqueline A
Sloane-Stanley Jacqueline A
Sutherland Linda
Meek Stephen
Burdon Tom
Gibbons Richard J
Garrick David
Higgs Douglas R
References (44)
44 references, click to expand
  1. Manipulating the mouse genome to engineer precise functional syntenic replacements with human sequence.
    Cell. 2007 Jan 12;128(1):197-209 PMID: 17218265
  2. High-efficiency FLP and PhiC31 site-specific recombination in mammalian cells.
    PLoS One. 2007 Jan 17;2(1):e162 PMID: 17225864
  3. Cold-induced silencing by long antisense transcripts of an Arabidopsis Polycomb target.
    Nature. 2009 Dec 10;462(7274):799-802 PMID: 20010688
  4. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells.
    Cell. 1987 Nov 6;51(3):503-12 PMID: 2822260
  5. Human DNA methylomes at base resolution show widespread epigenomic differences.
    Nature. 2009 Nov 19;462(7271):315-22 PMID: 19829295
  6. Genetics. It's the sequence, stupid!
    Science. 2008 Oct 17;322(5900):380-1 PMID: 18927376
  7. Globin gene activation during haemopoiesis is driven by protein complexes nucleated by GATA-1 and GATA-2.
    EMBO J. 2004 Jul 21;23(14):2841-52 PMID: 15215894
  8. Genomic strategies to identify mammalian regulatory sequences.
    Nat Rev Genet. 2001 Feb;2(2):100-9 PMID: 11253049
  9. Dnmt3a-dependent nonpromoter DNA methylation facilitates transcription of neurogenic genes.
    Science. 2010 Jul 23;329(5990):444-8 PMID: 20651149
  10. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a.
    Mol Cell. 2010 Jun 11;38(5):662-74 PMID: 20541999
  11. CpG islands influence chromatin structure via the CpG-binding protein Cfp1.
    Nature. 2010 Apr 15;464(7291):1082-6 PMID: 20393567
  12. Functional tests of enhancer conservation between distantly related species.
    Development. 2003 Nov;130(21):5133-42 PMID: 12944426
  13. Vernalization-mediated epigenetic silencing by a long intronic noncoding RNA.
    Science. 2011 Jan 7;331(6013):76-9 PMID: 21127216
  14. Species-specific transcription in mice carrying human chromosome 21.
    Science. 2008 Oct 17;322(5900):434-8 PMID: 18787134
  15. Capture of authentic embryonic stem cells from rat blastocysts.
    Cell. 2008 Dec 26;135(7):1287-98 PMID: 19109897
  16. GC-rich sequence elements recruit PRC2 in mammalian ES cells.
    PLoS Genet. 2010 Dec 09;6(12):e1001244 PMID: 21170310
  17. AEBP2 as a potential targeting protein for Polycomb Repression Complex PRC2.
    Nucleic Acids Res. 2009 May;37(9):2940-50 PMID: 19293275
  18. Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation.
    Mol Cell. 2008 Oct 24;32(2):232-46 PMID: 18951091
  19. Control of developmental regulators by Polycomb in human embryonic stem cells.
    Cell. 2006 Apr 21;125(2):301-13 PMID: 16630818
  20. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation.
    Genes Dev. 2004 Nov 1;18(21):2627-38 PMID: 15520282
  21. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells.
    Nature. 2007 Aug 2;448(7153):553-60 PMID: 17603471
  22. The Polycomb complex PRC2 and its mark in life.
    Nature. 2011 Jan 20;469(7330):343-9 PMID: 21248841
  23. Cis-acting sequences regulating expression of the human alpha-globin cluster lie within constitutively open chromatin.
    Cell. 1992 May 29;69(5):781-93 PMID: 1591777
  24. The role of the polycomb complex in silencing alpha-globin gene expression in nonerythroid cells.
    Blood. 2008 Nov 1;112(9):3889-99 PMID: 18689541
  25. Chromatin signatures of pluripotent cell lines.
    Nat Cell Biol. 2006 May;8(5):532-8 PMID: 16570078
  26. Generation of bivalent chromatin domains during cell fate decisions.
    Epigenetics Chromatin. 2011 Jun 06;4(1):9 PMID: 21645363
  27. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains.
    PLoS Genet. 2008 Oct;4(10):e1000242 PMID: 18974828
  28. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs.
    Cell. 2007 Jun 29;129(7):1311-23 PMID: 17604720
  29. A bivalent chromatin structure marks key developmental genes in embryonic stem cells.
    Cell. 2006 Apr 21;125(2):315-26 PMID: 16630819
  30. PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos.
    Nat Genet. 2008 Apr;40(4):411-20 PMID: 18311137
  31. A region of the human HOXD cluster that confers polycomb-group responsiveness.
    Cell. 2010 Jan 8;140(1):99-110 PMID: 20085705
  32. Genome-wide chromatin maps derived from limited numbers of hematopoietic progenitors.
    Nat Methods. 2010 Aug;7(8):615-8 PMID: 20622861
  33. Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling.
    Dev Cell. 2002 Oct;3(4):499-510 PMID: 12408802
  34. Number of CpG islands and genes in human and mouse.
    Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11995-9 PMID: 7505451
  35. Mapping and analysis of chromatin state dynamics in nine human cell types.
    Nature. 2011 May 5;473(7345):43-9 PMID: 21441907
  36. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome.
    Science. 2008 Oct 31;322(5902):750-6 PMID: 18974356
  37. Polycomb complexes repress developmental regulators in murine embryonic stem cells.
    Nature. 2006 May 18;441(7091):349-53 PMID: 16625203
  38. A vertebrate Polycomb response element governs segmentation of the posterior hindbrain.
    Cell. 2009 Sep 4;138(5):885-97 PMID: 19737517
  39. Cosuppression in Drosophila: gene silencing of Alcohol dehydrogenase by white-Adh transgenes is Polycomb dependent.
    Cell. 1997 Aug 8;90(3):479-90 PMID: 9267028
  40. Genomic maps and comparative analysis of histone modifications in human and mouse.
    Cell. 2005 Jan 28;120(2):169-81 PMID: 15680324
  41. Annotation of cis-regulatory elements by identification, subclassification, and functional assessment of multispecies conserved sequences.
    Proc Natl Acad Sci U S A. 2005 Jul 12;102(28):9830-5 PMID: 15998734
  42. Efficient gene targeting by homologous recombination in rat embryonic stem cells.
    PLoS One. 2010 Dec 03;5(12):e14225 PMID: 21151976
  43. Antagonism between DNA and H3K27 methylation at the imprinted Rasgrf1 locus.
    PLoS Genet. 2008 Aug 01;4(8):e1000145 PMID: 18670629
  44. Initial sequencing and comparative analysis of the mouse genome.
    Nature. 2002 Dec 5;420(6915):520-62 PMID: 12466850
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2011.399
Published
2012-01-18
Epub
2011-00-04
Pages
317-29
Language
English
Region
England
NLM ID
8208664
PMCID
PMC3261560
Subset
IM
Grants
Biotechnology and Biological Sciences Research Council · BBS/E/R/00001601 · United Kingdom
Biotechnology and Biological Sciences Research Council · BBS/E/R/00001627 · United Kingdom
Medical Research Council · MC_U137961147 · United Kingdom
Databases
GEO
GSE27580
External Links
PubMed source DOI: 10.1038/emboj.2011.399 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2