title: The Promyelocytic Leukemia Zinc Finger Transcription Factor Is Critical for Human Endometrial Stromal Cell Decidualization.
abstract: Progesterone, via the progesterone receptor (PGR), is essential for endometrial stromal cell decidualization, a cellular transformation event in which stromal fibroblasts differentiate into decidual cells. Uterine decidualization supports embryo implantation and placentation as well as subsequent events, which together ensure a successful pregnancy. Accordingly, impaired decidualization results not only in implantation failure or early fetal miscarriage, but also may lead to potential adverse outcomes in all three pregnancy trimesters. Transcriptional reprogramming on a genome-wide scale underlies progesterone dependent decidualization of the human endometrial stromal cell (hESC). However, identification of the functionally essential signals encoded by these global transcriptional changes remains incomplete. Importantly, this knowledge-gap undercuts future efforts to improve diagnosis and treatment of implantation failure based on a dysfunctional endometrium. By integrating genome-wide datasets derived from decidualization of hESCs in culture, we reveal that the promyelocytic leukemia zinc finger (PLZF) transcription factor is rapidly induced by progesterone and that this induction is indispensable for progesterone-dependent decidualization. Chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) identified at least ten progesterone response elements within the PLZF gene, indicating that PLZF may act as a direct target of PGR signaling. The spatiotemporal expression profile for PLZF in both the human and mouse endometrium offers further support for stromal PLZF as a mediator of the progesterone decidual signal. To identify functional targets of PLZF, integration of PLZF ChIP-Seq and RNA Pol II RNA-Seq datasets revealed that the early growth response 1 (EGR1) transcription factor is a PLZF target for which its level of expression must be reduced to enable progesterone dependent hESC decidualization. Apart from furnishing essential insights into the molecular mechanisms by which progesterone drives hESC decidualization, our findings provide a new conceptual framework that could lead to new avenues for diagnosis and/or treatment of adverse reproductive outcomes associated with a dysfunctional uterus.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Kommagani
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Szwarc
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Yasmin M
authors.initials: YM
authors.lastname: Vasquez
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Peavey
authors.affiliation: Houston Fertility Specialists, Houston, Texas, United States of America.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Mazur
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: William E
authors.initials: WE
authors.lastname: Gibbons
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Rainer B
authors.initials: RB
authors.lastname: Lanz
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Lydon
mesh_terms: D003656:Decidua / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051766:Early Growth Response Protein 1 / Q000235:genetics; D004717:Endometrium / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D011372:Progestins / Q000494:pharmacology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011980:Receptors, Progesterone / Q000502:physiology; D017154:Stromal Cells / Q000166:cytology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D051741:Kruppel-Like Transcription Factors; D011372:Progestins; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011980:Receptors, Progesterone; C092037:ZBTB16 protein, human