title: FOXO1 is required for binding of PR on IRF4, novel transcriptional regulator of endometrial stromal decidualization.
abstract: The forkhead box O1A (FOXO1) is an early-induced target of the protein kinase A pathway during the decidualization of human endometrial stromal cells (HESCs). In this study we identified the cistrome and transcriptome of FOXO1 and its role as a transcriptional regulator of the progesterone receptor (PR). Direct targets of FOXO1 were identified by integrating RNA sequencing with chromatin immunoprecipitation followed by deep sequencing. Gene ontology analysis demonstrated that FOXO1 regulates a subset of genes in decidualization such as those involved in cancer, p53 signaling, focal adhesions, and Wnt signaling. An overlap of the FOXO1 and PR chromatin immunoprecipitation followed by deep sequencing intervals revealed the co-occupancy of FOXO1 in more than 75% of PR binding intervals. Among these intervals were highly enriched motifs for the interferon regulatory factor member 4 (IRF4). IRF4 was determined to be a genomic target of both FOXO1 and PR and also to be differentially regulated in HESCs treated with small interfering RNA targeting FOXO1 or PR prior to decidualization stimulus. Ablation of FOXO1 was found to abolish binding of PR to the shared binding interval downstream of the IRF4 gene. Finally, small interfering RNA-mediated ablation of IRF4 was shown to compromise morphological transformation of decidualized HESCs and to attenuate the expression of the decidual markers IGFBP1, PRL, and WNT4. These results provide the first evidence that FOXO1 is functionally required for the binding of PR to genomic targets. Most notably, FOXO1 and PR are required for the regulation of IRF4, a novel transcriptional regulator of decidualization in HESCs.
authors.affiliation: Departments of Molecular and Cellular Biology (Y.M.V., X.L., R.K., R.B.L., F.J.D.) and Molecular and Human Genetics (L.J., R.C.), Baylor College of Medicine, and Division of Reproductive Endocrinology and Infertility (E.C.M., E.K., W.E.G.), Department of Obstetrics and Gynecology, Texas Children's Hospital Pavilion for Women, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Yasmin M
authors.initials: YM
authors.lastname: Vasquez
authors.forename: Erik C
authors.initials: EC
authors.lastname: Mazur
authors.forename: Xilong
authors.initials: X
authors.lastname: Li
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Kommagani
authors.forename: Lichun
authors.initials: L
authors.lastname: Jiang
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Rainer B
authors.initials: RB
authors.lastname: Lanz
authors.forename: Ertug
authors.initials: E
authors.lastname: Kovanci
authors.forename: William E
authors.initials: WE
authors.lastname: Gibbons
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D047369:Chromatin Immunoprecipitation; D003656:Decidua / Q000166:cytology* / Q000378:metabolism*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism*; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D012984:Software; D017154:Stromal Cells / Q000378:metabolism; D014158:Transcription, Genetic; D000099218:Interferon Regulatory Factor-4
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D050835:Interferon Regulatory Factors; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; D000099218:Interferon Regulatory Factor-4; C085126:FOXO1 protein, human