title: Dynamic Regulation of AP-1 Transcriptional Complexes Directs Trophoblast Differentiation.
abstract: Placentation is a process that establishes the maternal-fetal interface and is required for successful pregnancy. The epithelial component of the placenta consists of trophoblast cells, which possess the capacity for multilineage differentiation and are responsible for placenta-specific functions. FOS-like antigen 1 (FOSL1), a component of AP-1 transcription factor complexes, contributes to the regulation of placental development. FOSL1 expression is restricted to trophoblast giant cells and invasive trophoblast cells. In the present study, we characterized the FOSL1 regulatory pathway in rat trophoblast cells. Transcriptome profiling in control and FOSL1 knockdown cells identified FOSL1-dependent gene sets linked to endocrine and invasive functions. FOSL1 was shown to occupy AP-1 binding sites within these gene loci, as determined by chromatin immunoprecipitation (ChIP). Complementary in vivo experiments using trophoblast-specific lentiviral delivery of FOSL1 short hairpin RNAs (shRNAs) provided in vivo validation of FOSL1 targets. FOSL1 actions require a dimerization partner. Coimmunoprecipitation, coimmunolocalization, and ChIP analyses showed that FOSL1 interacts with JUNB and, to a lesser extent, JUN in differentiating trophoblast cells. Knockdown of FOSL1 and JUNB expression inhibited both endocrine and invasive properties of trophoblast cells. In summary, FOSL1 recruits JUNB to form AP-1 transcriptional complexes that specifically regulate the endocrine and invasive trophoblast phenotypes.
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA kkubota@kumc.edu msoares@kumc.edu.
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Kent
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: M A Karim
authors.initials: MA
authors.lastname: Rumi
authors.affiliation: Department of Anatomy and Cell Biology, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Katherine F
authors.initials: KF
authors.lastname: Roby
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA kkubota@kumc.edu msoares@kumc.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Soares
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D010929:Placentation / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014327:Trophoblasts / Q000166:cytology*; D000099169:Fos-Related Antigen 1
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1