Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium.
The eutopic endometrium in women with endometriosis demonstrates diminished endometrial receptivity and altered gene expression. It is unknown if the endometrium being defective gives rise to a predisposition toward endometriosis and infertility or, alternatively, if endometriosis causes the altered endometrial receptivity. Here we created experimental endometriosis in mice and examined the expression of several markers of endometrial receptivity in the eutopic endometrium. Methylation of Hoxa10 was also evaluated as a potential mechanism responsible for altered gene expression. Expression of each gene was measured using quantitative real-time RT-PCR at 14 wk after induction of endometriosis. Expression of Hoxa10 and Hoxa11, which are necessary for endometrial receptivity, were decreased in the endometriosis group. Insulin-like growth factor binding protein-1 (Igfbp1) mRNA was decreased in the endometriosis group. However, there was no change in Integrin beta3 (Itgb3) mRNA expression. Total progesterone receptor (Pgr-AB) was increased in the endometriosis group and the ratio of Pgr-B to Pgr-AB was increased, indicating a shift from Pgr-A to Pgr-B expression. Basic transcription element-binding protein-1 (Bteb1), official symbol and name Klf9, Kruppel-like factor 9, which functionally interacts with Pgr in endometrium, was also decreased in the endometriosis group. In addition, hypermethylation of Hoxa10 in the endometriosis group was shown by methylation-specific PCR and confirmed by bisulfite sequencing. These findings demonstrate that normal endometrium, when placed in an ectopic location to create experimental endometriosis, led to characteristic changes in gene expression in eutopic endometrium. These data suggest the existence of a signal conduction pathway from endometriosis that alters endometrial gene expression through altered Pgr signaling and epigenetic programming.
Lee
Banghyun
B
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Du
Hongling
H
Taylor
Hugh S
HS
D000818:Animals; D019175:DNA Methylation; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism; D004717:Endometrium / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D007150:Immunohistochemistry; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000096:biosynthesis / Q000235:genetics; D039641:Integrin beta Chains / Q000096:biosynthesis / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C094041:Hoxa11 protein, mouse; D018970:Insulin-Like Growth Factor Binding Protein 1; D039641:Integrin beta Chains; C489675:Klf9 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D011980:Receptors, Progesterone; C092119:Hoxa10 protein, mouse
Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9744-9
12897242
Methods Mol Biol. 2007;402:371-84
17951806
Mol Hum Reprod. 2007 May;13(5):323-32
17350963
Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1827-31
1542678
Semin Reprod Med. 2007 Nov;25(6):431-6
17960527
Biol Reprod. 1997 Dec;57(6):1338-45
9408238
Mol Endocrinol. 2002 Mar;16(3):571-9
11875117
J Biol Chem. 1994 Apr 22;269(16):11945-9
8163495
Nat Rev Genet. 2005 Aug;6(8):597-610
16136652
Am J Obstet Gynecol. 1986 Nov;155(5):1109-13
3777056
Development. 1996 Sep;122(9):2687-96
8787743
Lancet. 2004 Nov 13-19;364(9447):1789-99
15541453
N Engl J Med. 2001 Jul 26;345(4):266-75
11474666
J Clin Endocrinol Metab. 1999 Aug;84(8):2963-71
10443705
Fertil Steril. 2003 Sep;80 Suppl 2:820-7
14505759
Nature. 1995 Mar 30;374(6521):460-3
7700356
Hum Reprod Update. 2006 Sep-Oct;12(5):641-9
16775193
Am J Obstet Gynecol. 1968 Jun 15;101(4):569-70
5690299
Semin Reprod Med. 2003 May;21(2):125-34
12917782
Fertil Steril. 2006 Mar;85(3):564-72
16500320
Endocrinology. 2007 Aug;148(8):3814-26
17510236
Hum Reprod. 1999 Dec;14(12):3107-11
10601104
Hum Reprod. 1999 Dec;14(12):2944-50
10601076
Recent Prog Horm Res. 1999;54:291-313; discussion 313-4
10548881
Mol Endocrinol. 1993 Oct;7(10):1244-55
8264658
J Biol Chem. 2004 Jul 9;279(28):29286-94
15117941
Mol Hum Reprod. 1999 Sep;5(9):866-73
10460226
Fertil Steril. 2005 Aug;84(2):492-9
16084895
Fertil Steril. 2000 Jul;74(1):41-8
10899495
DNA Cell Biol. 2002 Nov;21(11):819-25
12489992
Gene Ther. 2000 Aug;7(16):1378-84
10981664
Genes Dev. 1995 Sep 15;9(18):2266-78
7557380
Reprod Biol Endocrinol. 2004 Jun 16;2:34
15200677
Endocrinology. 2002 Jan;143(1):62-73
11751593
Fertil Steril. 1996 Mar;65(3):603-7
8774295
Biol Reprod. 1991 Sep;45(3):411-6
1838282
Dev Dyn. 2007 Apr;236(4):1144-56
17304537
Trends Genet. 2007 Aug;23(8):413-8
17559965
Fertil Steril. 2002 Jun;77(6):1148-55
12057720
Mol Endocrinol. 1999 Jun;13(6):1005-17
10379898
J Clin Endocrinol Metab. 1999 Mar;84(3):1129-35
10084606
Hum Reprod. 1999 May;14(5):1328-31
10325287
Am J Obstet Gynecol. 2005 Aug;193(2):371-80
16098858
Ann N Y Acad Sci. 2008 Apr;1127:106-15
18443337
Biol Reprod. 2003 Jan;68(1):24-30
12493691
J Biol Chem. 2003 Jun 13;278(24):21474-82
12672823
Fertil Steril. 2007 Jan;87(1):24-32
17081533
Methods. 2001 Dec;25(4):402-8
11846609
J Clin Endocrinol Metab. 1994 Aug;79(2):643-9
7519194
Am J Pathol. 1985 Nov;121(2):337-41
4061568
Science. 2000 Sep 8;289(5485):1751-4
10976068
Horm Res. 1999;52(1):30-4
10640897
J Clin Endocrinol Metab. 2002 Oct;87(10):4782-91
12364474
Reprod Toxicol. 1995 May-Jun;9(3):233-8
7579907
Mol Carcinog. 2001 Dec;32(4):213-9
11746833
Dev Biol. 1998 May 15;197(2):141-54
9630742
J Clin Invest. 1998 Apr 1;101(7):1379-84
9525980
Endocrinology. 1989 Aug;125(2):930-4
2666107
Ups J Med Sci. 1984;89(2):129-34
6464242
Development. 1995 May;121(5):1373-85
7789268
BMJ. 2000 May 27;320(7247):1449-52
10827052