HOXA10 inhibits Kruppel-like factor 9 expression in the human endometrial epithelium.
Kruppel-like factor 9 (KLF9) is a zinc finger transcription factor that regulates estrogen and progesterone action by modulating the activity of progesterone receptor (PGR). The transition from proliferative to secretory endometrial epithelium involves loss of estrogen receptor/PGR expression and loss of direct response to sex steroids. HOXA10 partially mediates progesterone responsiveness in the endometrium. Here, we demonstrate that HOXA10 directly regulates KLF9 in endometrial epithelial cells and not in stromal cells. Immunohistochemistry performed on endometrial tissue obtained from normal, reproductive-age women revealed that KLF9 expression was decreased in the secretory phase of the menstrual cycle compared to the proliferative phase. In vitro, HOXA10 transfection of human endometrial epithelial cells (Ishikawa), but not stromal cells (HESC), resulted in a greater than 50% decrease in KLF9 mRNA and protein expression. Reporter constructs driven by the KLF9 promoter were repressed by cotransfection with HOXA10. Electrophoretic mobility shift assay was used to demonstrate direct binding of HOXA10 to the KLF9 promoter. Targeted mutation of the HOXA10-binding site in the KLF9 promoter resulted in loss of HOXA10 binding and loss of repression by HOXA10 in reporter assays. HOXA10 directly and selectively repressed KLF9 expression in endometrial epithelial cells. HOXA10 repression of KLF9 likely contributes to the loss of sex steroid responsiveness in secretory-phase endometrial epithelium.
Du
Hongling
H
Department of Obstetrics, Yale University, New Haven, Connecticut 06520, USA.
Sarno
Jennifer
J
Taylor
Hugh S
HS
D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004717:Endometrium / Q000737:chemistry / Q000378:metabolism*; D004848:Epithelium / Q000737:chemistry / Q000378:metabolism; D005260:Female; D005498:Follicular Phase; D015870:Gene Expression / Q000187:drug effects*; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000032:analysis / Q000235:genetics*; D008183:Luteal Phase; D016296:Mutagenesis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017154:Stromal Cells / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; C069634:HOXA10 protein, human
Biol Reprod. 1997 Oct;57(4):707-14
9314570
Biol Reprod. 2005 Sep;73(3):472-81
15917344
Mol Endocrinol. 2005 Sep;19(9):2222-33
15905361
Mol Endocrinol. 2007 Dec;21(12):2988-3001
17717078
J Mol Biol. 2004 Jul 23;340(5):1013-23
15236964
Mol Reprod Dev. 2004 Jan;67(1):8-14
14648870
J Biol Chem. 2004 Jul 9;279(28):29286-94
15117941
Endocrinology. 2004 May;145(5):2291-6
14726435
Gene Ther. 2000 Aug;7(16):1378-84
10981664
FASEB J. 2000 Jun;14(9):1101-8
10834931
J Endocrinol. 2009 Jan;200(1):63-73
18835980
Am J Pathol. 1988 Apr;131(1):112-24
3281468
J Clin Invest. 1998 Apr 1;101(7):1379-84
9525980
Biol Reprod. 1997 Dec;57(6):1338-45
9408238
Mol Endocrinol. 2002 Mar;16(3):571-9
11875117
Endocrinology. 2006 Apr;147(4):1969-78
16384861
Hum Reprod. 2008 Dec;23(12):2782-90
18775884
Int J Biochem Cell Biol. 2000 Nov-Dec;32(11-12):1103-21
11137451
Dev Dyn. 2001 Nov;222(3):538-44
11747087
Endocrinology. 2002 Jan;143(1):62-73
11751593
Reprod Biol Endocrinol. 2008 Sep 10;6:41
18783612
Mol Endocrinol. 1999 Jun;13(6):1005-17
10379898
J Clin Endocrinol Metab. 1999 Mar;84(3):1129-35
10084606
EMBO J. 1992 Oct;11(10):3663-71
1356762
J Biol Chem. 2003 Jun 13;278(24):21474-82
12672823
Biol Reprod. 2003 Jan;68(1):24-30
12493691
Methods. 2001 Dec;25(4):402-8
11846609
J Clin Endocrinol Metab. 1994 Aug;79(2):643-9
7519194
Mol Endocrinol. 2005 Nov;19(11):2839-46
15994197
Mol Cell Biol. 2003 Jan;23(1):1-13
12482956
Fertil Steril. 2003 Sep;80 Suppl 2:839-43
14505762
Acta Histochem. 2004;106(3):245-52
15186931