Nuclear Receptor,Coregulator Signaling,and Chromatin Remodeling Pathways Suggest Involvement of the Epigenome in the Steroid Hormone Response of Endometrium and Abnormalities in Endometriosis
Restricted accessResearch articleFirst published online February, 2012
Nuclear Receptor,Coregulator Signaling,and Chromatin Remodeling Pathways Suggest Involvement of the Epigenome in the Steroid Hormone Response of Endometrium and Abnormalities in Endometriosis
Human endometrium, a steroid hormone-dependent tissue, displays complex cellular regulation mediated by nuclear receptors (NRs). The NRs interact with histone-modifying and DNA-methylating/-demethylating enzymes in the transcriptional complex. We investigated NRs, their coregulators, and associated signaling pathways in endometrium across the normal menstrual cycle and in endometriosis, an estrogen-dependent, progesterone-resistant disorder. Endometrial tissue was processed for analysis of 84 genes using NR and coregulator polymerase chain reaction (PCR) arrays. Select genes were validated by immunohistochemistry. Ingenuity pathway analysis identified DNA methylation and transcriptional repression signaling as the most affected pathway in endometrium in women with versus without endometriosis, regardless of cycle phase. Thyroid hormone receptor (THR) and vitamin D receptor (VDR) pathways were also regulated in normal and disease endometrium by activation of TH or vitamin D regulated genes. These data support the involvement of the epigenome in steroid hormone response of normal endometrium throughout the cycle and abnormalities in endometrium in women with endometriosis.
AuboeufDDowhanDHDutertreMMartinNBergetSMO'MalleyBW. A subset of nuclear receptor coregulators act as coupling proteins during synthesis and maturation of RNA transcripts. Mol Cell Biol. 2005;25(13):5307–5316.
2.
FitzpatrickDRWilsonCB. Methylation and demethylation in the regulation of genes, cells, and responses in the immune system. Clin Immunol. 2003;109(1):37–45.
3.
FuksF. DNA methylation and histone modifications: teaming up to silence genes. Curr Opin Genet Dev. 2005;15(5):490–495.
4.
GiudiceLC.Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–2398.
5.
EskenaziBWarnerML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24(2):235–258.
6.
BulunSE. Endometriosis. N Engl J Med. 2009;360(3):268–279.
7.
AghajanovaLVelardeMCGiudiceLC. Altered gene expression profiling in endometrium: evidence for progesterone resistance. Semin Reprod Med. 2010;28(1):51–58.
8.
BainDLHeneghanAFConnaghan-JonesKDMiuraMT. Nuclear receptor structure: implications for function. Annu Rev Physiol. 2007;69:201–220.
9.
BulunSEChengYHYinPProgesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006;248(1-2):94–103.
10.
WuYStrawnEBasirZHalversonGGuoSW. Promoter hypermethylation of progesterone receptor isoform B (PR-B) in endometriosis. Epigenetics. 2006;1(2):106–111.
11.
AghajanovaLVelardeMCGiudiceLC. The progesterone receptor coactivator Hic-5 is involved in the pathophysiology of endometriosis. Endocrinology. 2009;150(8):3863–3870.
12.
BurneyROTalbiSHamiltonAEGene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148(8):3814–3826.
13.
AghajanovaLGiudiceLC. Molecular evidence for differences in endometrium in severe versus mild endometriosis. Reprod Sci. 2011;18(3):229–251.
14.
ChuangHCChangCWChangGDYaoTPChenH. Histone deacetylase 3 binds to and regulates the GCMa transcription factor. Nucleic Acids Res. 2006;34(5):1459–1469.
15.
NakaiASeinoSSakuraiASzilakIBellGIDeGrootLJ. Characterization of a thyroid hormone receptor expressed in human kidney and other tissues. Proc Natl Acad Sci U S A. 1988;85(8):2781–2785.
16.
WangQFujiiHKnippGT. Expression of PPAR and RXR isoforms in the developing rat and human term placentas. Placenta. 2002;23(8-9):661–671.
17.
KurookaHHonjoT. Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5. J Biol Chem. 2000;275(22):17211–17220.
18.
LeoCChenJD. The SRC family of nuclear receptor coactivators. Gene. 2000;245(1):1–11.
19.
WilsonBJBatesGJNicolSMGregoryDJPerkinsNDFuller-PaceFV. The p68 and p72 DEAD box RNA helicases interact with HDAC1 and repress transcription in a promoter-specific manner. BMC Mol Biol. 2004;5:11.
20.
AghajanovaLStavreus-EversALindebergMLandgrenBMSparreLSHovattaO. Thyroid-stimulating hormone receptor and thyroid hormone receptors are involved in human endometrial physiology. Fertil Steril. 2011;95(1):230–237 e232.
21.
HessANayakNGiudiceL. Oviduct and endometrium: cyclic changes in primate oviduct and endometrium. In: KnobilENeillJ, eds. The Physiology of Reproduction. San Diego: Academic Press; 2005:337–381.
22.
VienonenAMiettinenSBlauerMExpression of nuclear receptors and cofactors in human endometrium and myometrium. J Soc Gynecol Investig. 2004;11(2):104–112.
23.
ShiozawaTShihHCMiyamotoTCyclic changes in the expression of steroid receptor coactivators and corepressors in the normal human endometrium. J Clin Endocrinol Metab. 2003;88(2):871–878.
24.
WieserFSchneebergerCHudelistGEndometrial nuclear receptor co-factors SRC-1 and N-CoR are increased in human endometrium during menstruation. Mol Hum Reprod. 2002;8(7):644–650.
25.
CatalanoRDCritchleyHOHeikinheimoOMifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007;13(9):641–654.
26.
LiuXFBagchiMK. Recruitment of distinct chromatin-modifying complexes by tamoxifen-complexed estrogen receptor at natural target gene promoters in vivo. J Biol Chem. 2004;279(15):15050–15058.
27.
Hodges-GallagherLValentineCDBaderSEKushnerPJ. Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells. Breast Cancer Res Treat. 2007;105(3):297–309.
28.
KruscheCAVloetAJClassen-LinkeIvon RangoUBeierHMAlferJ. Class I histone deacetylase expression in the human cyclic endometrium and endometrial adenocarcinomas. Hum Reprod. 2007;22(11):2956–2966.
29.
TalbiSHamiltonAEVoKCMolecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology. 2006;147(3):1097–1121.
30.
MunroSKFarquharCMMitchellMDPonnampalamAP. Epigenetic regulation of endometrium during the menstrual cycle. Mol Hum Reprod. 2010;16(5):297–310.
31.
SuzukiAHoriuchiAOkaKMiyamotoTKashimaHShiozawaT. Immunohistochemical detection of steroid receptor cofactors in ovarian endometriosis: involvement of down-regulated SRC-1 expression in the limited growth activity of the endometriotic epithelium. Virchows Arch. 2010;456(4):433–441.
32.
UchikawaJShiozawaTShihHCExpression of steroid receptor coactivators and corepressors in human endometrial hyperplasia and carcinoma with relevance to steroid receptors and Ki-67 expression. Cancer. 2003;98(10):2207–2213.
33.
JacksonTARicherJKBainDLTakimotoGSTungLHorwitzKB. The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Mol Endocrinol. 1997;11(6):693–705.
34.
LiHLeoCSchroenDJChenJD. Characterization of receptor interaction and transcriptional repression by the corepressor SMRT. Mol Endocrinol. 1997;11(13):2025–2037.
35.
SmithCLNawazZO'MalleyBW. Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol. 1997;11(6):657–666.
36.
JacksonKSBrudneyAHastingsJMMavrogianisPAKimJJFazleabasAT. The altered distribution of the steroid hormone receptors and the chaperone immunophilin FKBP52 in a baboon model of endometriosis is associated with progesterone resistance during the window of uterine receptivity. Reprod Sci. 2007;14(2):137–150.
37.
DeMayoFJZhaoBTakamotoNTsaiSY. Mechanisms of action of estrogen and progesterone. Ann N Y Acad Sci. 2002;955:48-59; discussion 86-48, 396-406.
38.
XuJQiuYDeMayoFJTsaiSYTsaiMJO'MalleyBW. Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science. 1998;279(5358):1922–1925.
39.
Garcia-SilvaSArandaA. The thyroid hormone receptor is a suppressor of ras-mediated transcription, proliferation, and transformation. Mol Cell Biol. 2004;24(17):7514–7523.
40.
VelardeMCAghajanovaLNezhatCRGiudiceLC. Increased mitogen-activated protein kinase kinase/extracellularly regulated kinase activity in human endometrial stromal fibroblasts of women with endometriosis reduces 3',5'-cyclic adenosine 5'-monophosphate inhibition of cyclin D1. Endocrinology. 2009;150(10):4701–4712.
41.
JacobsAMNicolSMHislopRGJaffrayEGHayRTFuller-PaceFV. SUMO modification of the DEAD box protein p68 modulates its transcriptional activity and promotes its interaction with HDAC1. Oncogene. 2007;26(40):5866–5876.
42.
Fuller-PaceFV. DExD/H box RNA helicases: multifunctional proteins with important roles in transcriptional regulation. Nucleic Acids Res. 2006;34(15):4206–4215.
43.
EndohHMaruyamaKMasuhiroYPurification and identification of p68 RNA helicase acting as a transcriptional coactivator specific for the activation function 1 of human estrogen receptor alpha. Mol Cell Biol. 1999;19(8):5363–5372.
44.
ClarkELCoulsonADalglieshCThe RNA helicase p68 is a novel androgen receptor coactivator involved in splicing and is overexpressed in prostate cancer. Cancer Res. 2008;68(19):7938–7946.
45.
CarterCLLinCLiuCYYangLLiuZR. Phosphorylated p68 RNA helicase activates Snail1 transcription by promoting HDAC1 dissociation from the Snail1 promoter. Oncogene. 2010;29(39):5427–5436.
46.
Santos-RosaHCaldasC. Chromatin modifier enzymes, the histone code and cancer. Eur J Cancer. 2005;41(16):2381–2402.
GuoSW. Epigenetics of endometriosis. Mol Hum Reprod. 2009;15(10):587–607.
49.
TaylorHSAriciAOliveDIgarashiP. HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium. J Clin Invest. 1998;101(7):1379–1384.
