Jarid2 is a PRC2 component in embryonic stem cells required for multi-lineage differentiation and recruitment of PRC1 and RNA Polymerase II to developmental regulators.
Polycomb Repressor Complexes (PRCs) are important regulators of embryogenesis. In embryonic stem (ES) cells many genes that regulate subsequent stages in development are enriched at their promoters for PRC1, PRC2 and Ser 5-phosphorylated RNA Polymerase II (RNAP), and contain domains of 'bivalent' chromatin (enriched for H3K4me3; histone H3 di- or trimethylated at Lys 4 and H3K27me3; histone H3 trimethylated at Lys 27). Loss of individual PRC components in ES cells can lead to gene de-repression and to unscheduled differentiation. Here we show that Jarid2 is a novel subunit of PRC2 that is required for the co-recruitment of PRC1 and RNAP to genes that regulate development in ES cells. Jarid2-deficient ES cells showed reduced H3K4me2/me3 and H3K27me3 marking and PRC1/PRC2 recruitment, and did not efficiently establish Ser 5-phosporylated RNAP at target genes. ES cells lacking Jarid2, in contrast to previously characterized PRC1 and PRC2 mutants, did not inappropriately express PRC2 target genes. Instead, they show a severely compromised capacity for successful differentiation towards neural or mesodermal fates and failed to correctly initiate lineage-specific gene expression in vitro. Collectively, these data indicate that transcriptional priming of bivalent genes in pluripotent ES cells is Jarid2-dependent, and suggests that priming is critical for subsequent multi-lineage differentiation.
Landeira
David
D
Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN UK.
Sauer
Stephan
S
Poot
Raymond
R
Dvorkina
Maria
M
Mazzarella
Luca
L
Jørgensen
Helle F
HF
Pereira
C Filipe
CF
Leleu
Marion
M
Piccolo
Francesco M
FM
Spivakov
Mikhail
M
Brookes
Emily
E
Pombo
Ana
A
Fisher
Cynthia
C
Skarnes
William C
WC
Snoek
Tim
T
Bezstarosti
Karel
K
Demmers
Jeroen
J
Klose
Robert J
RJ
Casanova
Miguel
M
Tavares
Ligia
L
Brockdorff
Neil
N
Merkenschlager
Matthias
M
Fisher
Amanda G
AG
D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039904:Pluripotent Stem Cells / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin; D006657:Histones; D011506:Proteins; D012319:RNA Polymerase II
Nat Cell Biol. 2006 May;8(5):532-8
16570078
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2468-73
12589020
Nat Methods. 2009 Jul;6(7):493-5
19525957
Stem Cells. 2008 Jun;26(6):1496-505
18403752
Nat Genet. 2006 Apr;38(4):431-40
16518401
Mol Cell. 2004 Mar 26;13(6):887-93
15053881
Methods Enzymol. 2003;365:327-41
14696356
Mol Cell Biol. 2007 May;27(10):3769-79
17339329
Cell. 2008 Feb 8;132(3):422-33
18237772
PLoS Genet. 2008 Sep 05;4(9):e1000170
18773085
EMBO Rep. 2009 Nov;10(11):1213-9
19834511
Development. 2008 Apr;135(8):1513-24
18339675
Cell. 2008 Feb 22;132(4):567-82
18295576
Cell. 2009 Dec 24;139(7):1290-302
20064375
Development. 2003 Sep;130(17):4217-27
12874139
Genes Dev. 2010 Feb 15;24(4):368-80
20123894
Cell. 2008 Mar 21;132(6):1049-61
18358816
Cell Stem Cell. 2010 Apr 2;6(4):369-81
20362541
Cell. 2005 Sep 23;122(6):947-56
16153702
Dev Dyn. 2005 Jan;232(1):21-32
15580614
Cell. 2009 Dec 24;139(7):1303-14
20064376
Mol Cell. 2008 Nov 21;32(4):491-502
19026780
Development. 1995 Feb;121(2):273-85
7768172
Cell. 2006 Apr 21;125(2):301-13
16630818
J Cell Biol. 2009 Apr 6;185(1):27-34
19349578
Cell Cycle. 2006 Jul;5(13):1411-4
16855402
Dev Dyn. 2006 Sep;235(9):2449-59
16715513
Cell. 2006 Apr 21;125(2):233-6
16630812
Mol Cell. 2008 Jun 20;30(6):755-66
18514006
Cell. 2006 Apr 21;125(2):315-26
16630819
Cell. 2007 Jul 13;130(1):77-88
17632057
Mol Cell. 2004 Jul 2;15(1):57-67
15225548
Methods Enzymol. 2003;365:59-72
14696337
Nature. 2006 May 18;441(7091):349-53
16625203
Nature. 2010 Mar 11;464(7286):306-10
20075857
Nature. 2001 Aug 9;412(6847):651-5
11493924
Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13188-93
16129827
Nat Cell Biol. 2007 Dec;9(12):1428-35
18037880
EMBO J. 2004 Oct 13;23(20):4061-71
15385962
Mol Cell Biol. 2001 Jul;21(13):4330-6
11390661