Genome-wide DNA methylation analysis in cohesin mutant human cell lines.
The cohesin complex has recently been shown to be a key regulator of eukaryotic gene expression, although the mechanisms by which it exerts its effects are poorly understood. We have undertaken a genome-wide analysis of DNA methylation in cohesin-deficient cell lines from probands with Cornelia de Lange syndrome (CdLS). Heterozygous mutations in NIPBL, SMC1A and SMC3 genes account for ∼65% of individuals with CdLS. SMC1A and SMC3 are subunits of the cohesin complex that controls sister chromatid cohesion, whereas NIPBL facilitates cohesin loading and unloading. We have examined the methylation status of 27 578 CpG dinucleotides in 72 CdLS and control samples. We have documented the DNA methylation pattern in human lymphoblastoid cell lines (LCLs) as well as identified specific differential DNA methylation in CdLS. Subgroups of CdLS probands and controls can be classified using selected CpG loci. The X chromosome was also found to have a unique DNA methylation pattern in CdLS. Cohesin preferentially binds to hypo-methylated DNA in control LCLs, whereas the differential DNA methylation alters cohesin binding in CdLS. Our results suggest that in addition to DNA methylation multiple mechanisms may be involved in transcriptional regulation in human cells and in the resultant gene misexpression in CdLS.
Liu
Jinglan
J
Division of Human Genetics, Abramson Research Institute, Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Zhang
Zhe
Z
Bando
Masashige
M
Itoh
Takehiko
T
Deardorff
Matthew A
MA
Li
Jennifer R
JR
Clark
Dinah
D
Kaur
Maninder
M
Tatsuro
Kondo
K
Kline
Antonie D
AD
Chang
Celia
C
Vega
Hugo
H
Jackson
Laird G
LG
Spinner
Nancy B
NB
Shirahige
Katsuhiko
K
Krantz
Ian D
ID
D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D041321:Chromosomes, Human, X / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D019175:DNA Methylation; D003635:De Lange Syndrome / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D015894:Genome, Human; D006657:Histones / Q000378:metabolism; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012091:Repetitive Sequences, Nucleic Acid; D012984:Software; D000097722:Cohesins
D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004247:DNA; D006657:Histones; D000097722:Cohesins
Nature. 2007 Feb 8;445(7128):671-5
17268471
Annu Rev Biochem. 2005;74:595-648
15952899
Nat Genet. 2004 Jun;36(6):636-41
15146185
PLoS Comput Biol. 2007 Jun;3(6):e110
17559301
Nature. 2006 Feb 16;439(7078):871-4
16357870
Nat Genet. 2006 May;38(5):528-30
16604071
J Neurosci Res. 2009 Jul;87(9):1953-9
19224581
Nat Rev Mol Cell Biol. 2006 May;7(5):311-22
16633335
Nat Genet. 2003 Mar;33 Suppl:245-54
12610534
Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4844-9
18353987
PLoS Genet. 2006 Mar;2(3):e26
16520826
Nat Genet. 2004 Jun;36(6):631-5
15146186
Nature. 2009 Jul 16;460(7253):410-3
19458616
Differentiation. 2009 Jan;77(1):1-11
19281759
Gene. 1997 Aug 11;195(1):67-71
9300822
Genome Res. 2006 Aug;16(8):973-9
16809669
Nat Rev Genet. 2005 Aug;6(8):597-610
16136652
Mol Cell Biol. 2004 Apr;24(8):3100-11
15060134
J Immunol. 2006 Mar 1;176(5):2991-9
16493057
Hum Mol Genet. 2005 Feb 15;14(4):525-33
15640246
Genes Dev. 2002 Feb 15;16(4):399-414
11850403
Hum Mol Genet. 2009 Feb 1;18(3):418-27
18996922
Am J Hum Genet. 2007 Mar;80(3):485-94
17273969
Curr Genomics. 2009 Mar;10(1):64-75
19721813
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3443-8
18299561
Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3740-5
11891299
Annu Rev Genomics Hum Genet. 2008;9:303-20
18767966
Nature. 2007 Sep 13;449(7159):248-51
17713477
Nature. 2007 May 24;447(7143):425-32
17522676
Nature. 2008 Aug 7;454(7205):766-70
18600261
Nat Genet. 2006 Dec;38(12):1359-60
17133218
Trends Biochem Sci. 2006 Feb;31(2):89-97
16403636
Biochem Biophys Res Commun. 2005 Jun 17;331(4):929-37
15882967
Chromosoma. 2008 Feb;117(1):89-102
17965872
Genes Dev. 1998 Jun 15;12(12):1801-11
9637682
Nat Genet. 2008 May;40(5):663-9
18425126
Nat Genet. 2008 May;40(5):670-5
18425128
Science. 2007 Nov 16;318(5853):1136-40
18006746
Genetics. 1999 Jun;152(2):577-93
10353901
Cell. 1999 Nov 24;99(5):451-4
10589672
Nat Rev Genet. 2007 Feb;8(2):93-103
17230196
Am J Hum Genet. 2002 Oct;71(4):791-800
12226795
Genome Res. 2006 Sep;16(9):1075-83
16899657
Nature. 2008 Feb 14;451(7180):796-801
18235444
J Cell Biochem. 2002;87(2):117-25
12244565
PLoS Genet. 2009 Mar;5(3):e1000438
19325872
PLoS Biol. 2009 May 5;7(5):e1000119
19468298
PLoS Genet. 2007 Oct;3(10):2023-36
17967063
Genome Biol. 2009 Feb 10;10(2):R14
19208250
Genome Res. 2004 Feb;14(2):247-66
14762061
Nat Genet. 2006 Dec;38(12):1378-85
17072317
Nature. 2005 Mar 17;434(7031):400-4
15772666
Genes Dev. 2002 Jan 1;16(1):6-21
11782440
Biotechniques. 2002 Jun;Suppl:56-8, 60-1
12083399
Hum Mol Genet. 2007 Jun 15;16(12):1478-87
17468178