The Promyelocytic Leukemia Zinc Finger Transcription Factor Is Critical for Human Endometrial Stromal Cell Decidualization

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 ev...

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Bibliographic Details
Published in:PLoS genetics 2016-04, Vol.12 (4), p.e1005937
Main Authors: Kommagani, Ramakrishna, Szwarc, Maria M, Vasquez, Yasmin M, Peavey, Mary C, Mazur, Erik C, Gibbons, William E, Lanz, Rainer B, DeMayo, Francesco J, Lydon, John P
Format: Article
Language:English
Subjects:
Biology and life sciences
Decidua - cytology
Decidua - metabolism
Decidua - physiology
Early Growth Response Protein 1 - genetics
Embryos
Endometrium - cytology
Endometrium - metabolism
Female
Fibroblasts
Gene expression
Genetic aspects
Genomes
Health aspects
Humans
Kruppel-Like Transcription Factors - biosynthesis
Kruppel-Like Transcription Factors - physiology
Leukemia
Medicine and Health Sciences
Menstruation
Miscarriage
Pregnancy
Progestins - pharmacology
Promyelocytic Leukemia Zinc Finger Protein
Receptors, Progesterone - physiology
Reproductive technologies
Research and Analysis Methods
Stromal Cells - cytology
Stromal Cells - metabolism
Transcription (Genetics)
Transcription factors
Transcription, Genetic - physiology
Zinc
Zinc finger proteins
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Summary: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.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1005937