Hox genes have a well-characterized role in embryonic development, where they determine identity along the anteroposterior body axis. Hox genes are expressed not only during embryogenesis but also in the adult, where they are necessary for functional differentiation. Despite the known function of these genes as transcription factors, few regulatory mechanisms that drive Hox expression are known. Recently, several hormones and their cognate receptors have been shown to regulate Hox gene expression and thereby mediate development in the embryo as well as functional differentiation in the adult organism. Estradiol, progesterone, testosterone, retinoic acid, and vitamin D have been shown to regulate Hox gene expression. In the embryo, the endocrine system directs axial Hox gene expression; aberrant Hox gene expression due to exposure to endocrine disruptors contributes to the teratogenicity of these compounds. In the adult, endocrine regulation of Hox genes is necessary to enable such diverse functions as hematopoiesis and reproduction; endocrinopathies can result in dysregulated HOX gene expression affecting physiology. By regulating HOX genes, hormonal signals utilize a conserved mechanism that allows generation of structural and functional diversity in both developing and adult tissues. This review discusses endocrine Hox regulation and its impact on physiology and human pathology.
Vitamin D receptor (VDR) and the functionally active form of its ligand, 1,25-(OH)2D3, have been implicated in female reproduction function and myeloid leukemic cell differentiation. HOXA10 is necessary for embryo implantation and fertility, as well as hematopoeitic development. In this study, we identified a direct role of vitamin D in the regulation of HOXA10 in primary human endometrial stromal cells, the human endometrial stromal cell line (HESC), and in the human myelomonocytic cell line, U937. Treatment of primary endometrial stromal cells, or the cell lines HESC and U937 with 1,25-(OH)2D3 increased HOXA10 mRNA and protein expression. VDR mRNA and protein were detected in primary uterine stromal cells as well as HESC and U937 cells. We cloned the HOXA10 upstream regulatory sequence and two putative vitamin D response elements (VDRE) into luciferase reporter constructs and transfected primary stromal cells and HESC. One putative VDRE (P1: -385 to -434 bp upstream of HOXA10) drove reporter gene expression in response to treatment with 1,25-(OH)2D3. In EMSA, VDR demonstrated binding to the HOXA10 VDRE in the presence of 1,25-(OH)2D3. 1,25-(OH)2D3 up-regulates HOXA10 expression by binding VDR and interacting with a VDRE in the HOXA10 regulatory region. Direct regulation of HOXA10 by vitamin D has implications for fertility and myeloid differentiation.
HOXA10 is necessary for mammalian reproduction; however, its transcriptional targets are not completely defined. EMX2, a divergent homeobox gene, is necessary for urogenital tract development. In these studies we identify and characterize the regulation of EMX2 by HOXA10. By using Northern analysis and in situ hybridization, we found that EMX2 is expressed in the adult urogenital tract in an inverse temporal pattern from HOXA10
Estrogen and progesterone regulate HOXA10 expression in the endometrium, where HOXA10 is necessary for implantation. The integrins are also involved in early embryo-endometrial interactions. Here we show that HOXA10 directly regulates beta3-integrin subunit expression in the endometrium, likely mediating the effect of sex steroids on beta3-integrin expression. beta3-Integrin expression was decreased in endometrium shown to have low HOXA10 expression. beta3-Integrin mRNA levels were increased in endometrial adenocarcinoma cells (Ishikawa) transfected with pcDNA3.1/HOXA10, and decreased in cells treated with HOXA10 antisense. Seven consensus HOXA10 binding sites were identified 5' of the beta3-integrin gene. Direct binding of HOXA10 protein to four sites was demonstrated by EMSA. Reporter gene expression increased in BT-20 cells cotransfected with pcDNA3.1/ HOXA10 and pGL3-promoter vector containing region F (encompassing all seven HOXA10 consensus sites). A 41-bp segment (Region A) showed highest affinity binding to HOXA10 protein. Increased reporter expression, equal in magnitude to that obtained with Region F, was obtained with Region A. HOXA10 protein binding within Region A was localized by deoxyribonuclease I footprinting. beta3-Integrin expression was directly up-regulated by HOXA10 through a 41-bp 5'-regulatory element. Sex steroids regulate the expression of endometrial beta3-integrin through a pathway involving HOXA10.
EMX2 is a transcription factor necessary for reproductive tract development. Sex steroids regulate endometrial HOXA10 expression, which in turn negatively regulates EMX2. In this study, we characterize menstrual cycle-dependent expression of EMX2 in endometrium from women with and without endometriosis. In the absence of endometriosis, EMX2 mRNA levels declined 50% in periimplantation endometrium compared with levels in the proliferative phase. To determine whether the decrease in endometrial EMX2 expression was regulated by endogenous endometrial HOXA10, primary endometrial stromal cells were transfected with an EMX2-reporter construct containing a HOXA10 binding site. Acting via this site, we observed HOXA10-mediated repression of reporter expression. In the endometrium of patients with endometriosis, unlike normal endometrium, EMX2 levels were not decreased in the periimplantation period. We have previously shown that up-regulation of HOXA10 in periimplantation endometrium fails to occur in women with endometriosis. To determine whether elevated endometrial EMX2 levels were due to failure of HOXA10-mediated transcriptional repression, secondary to low HOXA10 levels in endometriosis, we transfected stromal cells with HOXA10 antisense and an EMX2-reporter construct. Reporter expression was increased, indicating reversal of HOXA10-mediated transcriptional repression. Endometrial EMX2 expression is aberrant in women with endometriosis and is mediated by altered HOXA10 expression.
Endometriosis affects approximately 10% of young, reproductive-aged women. Disease associated pelvic pain; infertility and sexual dysfunction have a significant adverse clinical, social and financial impact. As precise disease etiology has remained elusive, current therapeutic strategies are empiric, unfocused and often unsatisfactory. Lack of a suitable genetic model has impaired further translational research in the field. In this study, we evaluated the role of the Sp/KLF transcription factor KLF11/Klf11 in the pathogenesis of endometriosis. KLF11, a human disease-associated gene is etiologically implicated in diabetes, uterine fibroids and cancer. We found that KLF11 expression was diminished in human endometriosis implants and further investigated its pathogenic role in Klf11-/- knockout mice with surgically induced endometriotic lesions. Lesions in Klf11-/- animals were large and associated with prolific fibrotic adhesions resembling advanced human disease in contrast to wildtype controls. To determine phenotype-specificity, endometriosis was also generated in Klf9-/- animals. Unlike in Klf11-/- mice, lesions in Klf9-/- animals were neither large, nor associated with a significant fibrotic response. KLF11 also bound to specific elements located in the promoter regions of key fibrosis-related genes from the Collagen, MMP and TGF-β families in endometrial stromal cells. KLF11 binding resulted in transcriptional repression of these genes. In summary, we identify a novel pathogenic role for KLF11 in preventing de novo disease-associated fibrosis in endometriosis. Our model validates in vivo the phenotypic consequences of dysregulated Klf11 signaling. Additionally, it provides a robust means not only for further detailed mechanistic investigation but also the ability to test any emergent translational ramifications thereof, so as to expand the scope and capability for treatment of endometriosis.
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