hoxa-11 and foxo1a cooperate to regulate decidual prolactin expression towards inferring the core transcriptional regulators of decidual geneshoxa-11和foxo1a配合调节蜕膜催乳激素的表达对推断核心蜕膜基因的转录监管机构.pdfVIP

HoxA-11 and FOXO1A Cooperate to Regulate Decidual Prolactin Expression: Towards Inferring the Core Transcriptional Regulators of Decidual Genes 1. 1. 2 ¨ 1 Vincent J. Lynch *, Kathryn Brayer , Birgit Gellersen , Gunter P. Wagner 1 Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, United States of America, 2 Endokrinologikum Hamburg, Hamburg, Germany Abstract Background: During the menstrual cycle, the ovarian steroid hormones estrogen and progesterone control a dramatic transcriptional reprogramming of endometrial stromal cells (ESCs) leading to a receptive state for blastocyst implantation and the establishment of pregnancy. A key marker gene of this decidualization process is the prolactin gene. Several transcriptional regulators have been identified that are essential for decidualization of ESCs, including the Hox genes HoxA- 10 and HoxA-11, and the forkhead box gene FOXO1A. While previous studies have identified downstream target genes for HoxA-10 and FOXO1A, the role of HoxA-11 in decidualization has not been investigated. Here, we show that HoxA-11 is required for prolactin expression in decidualized ESC. While HoxA-11 alone is a repressor on the decidual prolactin promoter, it turns into an activator when combined with FOXO1A. Conversely, HoxA-10, which has been previously shown to associate with FOXO1A to upregulate decidual IGFBP-1 expression, is unable to upregulate PRL expression when co- expressed with FOXO1A. By co-immunoprecipitation and chromatin immunoprecipitation, we demonstrate physical association of HoxA-11 and FOXO1A, and binding of both factors to an enhancer region ( 2395 to 2