HOXC and HOXD Gene Expression in Human Endometrium: Lack of Redundancy with HOXA Paralogs1

Abstract

HOXA genes, essential regulators of differentiation in the embryo, are also essential for adult cyclic endometrial development and for endometrial receptivity. Mice deficient in Hoxa10 or Hoxa11 exhibit reduced fertility because of defects in implantation. We hypothesized that HOXC10, HOXC11, HOXD10, and HOXD11, paralogs of HOXA10 and HOXA11, might also be involved in endometrial development. Here, we showed that the expression of HOXC10, HOXC11, HOXD10, and HOXD11 was evident throughout the menstrual cycle in the endometrium by semiquantitative reverse transcription-polymerase chain reaction. In the secretory phase, expression of HOXC10, HOXC11, and HOXD11 decreased to 4% and HOXD10 decreased to 25% of the proliferative phase expression (P < 0.001, P < 0.001, P < 0.02, P < 0.01, respectively). In situ hybridization demonstrated expression of each of these HOX genes primarily in the stroma and confirmed the decreased expression in the secretory phase. HOXC10, HOXC11, HOXD10, and HOXD11 expression was not regulated by sex steroids in primary endometrial stromal cells or Ishikawa cells. The expression and regulation of HOXC and HOXD genes varies from that of HOXA10 and HOXA11. Whereas HOXA10 and HOXA11 are regulators of endometrial differentiation, HOXC and HOXD genes likely regulate endometrial proliferation. Paralogous HOX genes typically have a redundant function in development; a novel evolutionary divergence of paralogous Hox genes has resulted in HOXC and HOXD genes having distinct expression patterns, regulation, and likely also distinct functions from HOXA genes. A network of HOX genes may be involved in regulating multiple aspects of endometrial development, including both proliferation and differentiation.

Genome-Wide DNA Methylation Analysis Predicts an Epigenetic Switch for GATA Factor Expression in Endometriosis

“…These genes show a consistent correlation between DNA methylation and gene expression which is altered in endometriosis, although their function in the endometrium remains largely unknown. HOXD10 has been implicated in endometrial stromal cell proliferation, and our pathway analysis comparison identified it as well, suggesting that all of the HOX clusters may show aberrant methylation in endometriosis [42].…”

Regulation of homeobox A10 expression in the primate endometrium by progesterone and embryonic stimuli

“…This observation indicates that HOXA11 transcription in the endometrium is not affected by embryonic stimuli and the expression of both these orthologs may not be strictly coregulated during the process of implantation. Indeed, no correlation has been found in expression profiles of HOX orthologs in human endometrium during different phases of menstrual cycle (Akbas & Taylor 2004), indicating a lack of redundancy and existence of independent regulatory mechanisms.…”

Endometrial biopsy-induced gene modulation: first evidence for the expression of bladder-transmembranal uroplakin Ib in human endometrium

“…Along this line, in vitro studies suggested that PGE2 and relaxin act via IL-11 to phosphorylate Stat3, which enhances P-induced decidualization in cultured human stromal cells (6). A decrease in genes from the HOX cluster such as hoxc10, hoxc11, hoxd10, and hoxd11 during the implantation window, which was also observed, suggests that these transcriptional repressors may interfere with the preparation of the endometrium for implantation (7).…”