Widespread DNA hypomethylation and differential gene expression in Turner syndrome.
Adults with 45,X monosomy (Turner syndrome) reflect a surviving minority since more than 99% of fetuses with 45,X monosomy die in utero. In adulthood 45,X monosomy is associated with increased morbidity and mortality, although strikingly heterogeneous with some individuals left untouched while others suffer from cardiovascular disease, autoimmune disease and infertility. The present study investigates the leukocyte DNAmethylation profile by using the 450K-Illumina Infinium assay and the leukocyte RNA-expression profile in 45,X monosomy compared with karyotypically normal female and male controls. We present results illustrating that genome wide X-chromosome RNA-expression profile, autosomal DNA-methylation profile, and the X-chromosome methylation profile clearly distinguish Turner syndrome from controls. Our results reveal genome wide hypomethylation with most differentially methylated positions showing a medium level of methylation. Contrary to previous studies, applying a single loci specific analysis at well-defined DNA loci, our results indicate that the hypomethylation extend to repetitive elements. We describe novel candidate genes that could be involved in comorbidity in TS and explain congenital urinary malformations (PRKX), premature ovarian failure (KDM6A), and aortic aneurysm formation (ZFYVE9 and TIMP1).
Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.|Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Christian
C
Trolle
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Morten Muhlig
MM
Nielsen
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
Anne
A
Skakkebæk
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Philippe
P
Lamy
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Søren
S
Vang
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Jakob
J
Hedegaard
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Iver
I
Nordentoft
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Torben Falck
TF
Ørntoft
Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.|Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
Jakob Skou
JS
Pedersen
Department of Endocrinology and Internal Medicine and Medical Research Laboratories, Aarhus University Hospital, Aarhus, Denmark.|Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
Claus Højbjerg
CH
Gravholt
Hum Genet. 1983;64(3):267-70
6224736
Curr Pharm Des. 2014;20(11):1778-85
23888970
Nat Genet. 2013 Sep;45(9):1083-7
23872635
Hum Genet. 2014 Sep;133(9):1075-82
24850140
Clin Exp Immunol. 2000 Jun;120(3):399-405
10844515
Biochim Biophys Acta. 2000 Jul 24;1492(2-3):522-5
11004523
Nat Genet. 2013 Oct;45(10):1198-206
23995138
Nature. 1989 Dec 21-28;342(6252):860-2
2512507
Clin Epigenetics. 2015 Jul 28;7:76
26221191
Genome Biol. 2010;11(8):216
20804581
Matrix Biol. 1999 Apr;18(2):121-4
10372551
Cytogenetics. 1964;3:355-83
14267131
Hum Mol Genet. 1997 Aug;6(8):1341-7
9259282
Nat Protoc. 2013 Sep;8(9):1765-86
23975260
Clin Exp Immunol. 2009 May;156(2):205-10
19298606
Nat Genet. 1993 Jul;4(3):268-71
8358435
Cell. 1990 Dec 21;63(6):1205-18
2124517
Hum Mutat. 2013 Jan;34(1):108-10
23076834
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2706-11
19202056
Epigenetics Chromatin. 2013 Mar 03;6(1):4
23452981
Am J Med Genet A. 2015 Sep;167A(9):1962-71
25920614
Nature. 2014 Apr 24;508(7497):494-9
24759411
Epigenetics. 2009 Aug 16;4(6):415-20
19755850
Nat Biotechnol. 2010 May;28(5):495-501
20436461
BMC Bioinformatics. 2010 Nov 30;11:587
21118553
Genomics. 1996 Jan 1;31(1):44-50
8808278
Hum Genet. 1992 May;89(2):240-2
1587534
Am J Med Genet. 2001 May 15;100(4):269-74
11343317
Hum Mol Genet. 2012 Jan 1;21(1):219-35
21972244
Am J Med Genet A. 2004 Jul 30;128A(3):276-84
15216549
BMC Genomics. 2014 Jan 17;15:33
24438232
Cell. 2006 Mar 10;124(5):915-27
16530040
Genes Dev. 2011 May 15;25(10):1010-22
21576262
Genome Biol. 2013 Nov 01;14(11):R122
24176135
PLoS Genet. 2013 May;9(5):e1003489
23658530
Nat Rev Genet. 2014 Jun;15(6):367-78
24733023
Genome Res. 2011 Oct;21(10):1592-600
21862626
Hum Genet. 1996 Jan;97(1):39-44
8557258
PLoS One. 2009;4(1):e4175
19137066
Am J Hum Genet. 2012 Jan 13;90(1):119-24
22197486
J Cardiovasc Magn Reson. 2011 Apr 28;13:24
21527014
BMC Genomics. 2013;14 Suppl 5:S8
24564826
Am J Hum Genet. 1998 Dec;63(6):1757-66
9837829
Cytogenet Genome Res. 2002;99(1-4):276-84
12900575
Am J Med Genet A. 2009 Oct;149A(10):2152-7
19764037
J Clin Endocrinol Metab. 2009 Sep;94(9):3289-96
19567529
Am J Physiol Endocrinol Metab. 2001 Feb;280(2):E308-14
11158935
BMC Bioinformatics. 2012 May 08;13:86
22568884
PLoS One. 2014 Jun 16;9(6):e100076
24932682
Bioinformatics. 2013 Nov 15;29(22):2884-91
23990415
Nature. 2015 Jan 15;517(7534):321-6
25592537
J Clin Invest. 2006 Oct;116(10):2817-26
17016562
Endocr Rev. 2012 Oct;33(5):677-714
22707402
Genome Biol. 2010;11(6):213
20573260
Epigenetics. 2010 Oct 1;5(7):612-8
20657171
J Clin Epidemiol. 1998 Feb;51(2):147-58
9474075
Mol Cell. 2012 Aug 24;47(4):633-47
22841485
Hiroshima J Med Sci. 2013 Sep;62(3):63-7
24279124
Bioinformatics. 2006 Jun 15;22(12):1540-2
16595560
J Am Soc Nephrol. 2005 Dec;16(12):3543-52
16236808