title: Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation.
abstract: Pregnancies resulting from fresh in vitro fertilization (IVF) cycles exposed to supraphysiologic estrogen levels have been associated with higher rates of low birth weight and small for gestational age babies. We identified GATA3, a transcription factor selectively expressed in the trophectoderm during the blastocyst stage of embryo development, in an upstream analysis of genes that were differentially methylated in chorionic villus samples between IVF and non-IVF infertility treatment pregnancies. In this study, we investigate the hypothesis that GATA3 is hormonally regulated and plays an important functional role in trophoblast migration, invasion, and placentation. We found that GATA3 expression was hormonally regulated by estradiol in HTR8/SVneo first trimester trophoblast cells; however, no change in expression was seen with progesterone treatment. Furthermore, GATA3 knockdown resulted in decreased HTR8/SVneo cell migration and invasion compared with controls. RNA sequencing of GATA3 knockdown cells demonstrated 96 differentially regulated genes compared with controls. Genes known to play an important role in cell-cell and cell-extracellular matrix interactions, cell invasion, and placentation were identified, including CTGF, CYR61, ADAMTS12, and TIMP3 Our results demonstrate estradiol down-regulates GATA3, and decreased GATA3 expression leads to impaired trophoblast cell migration and invasion, likely through regulation of downstream genes important in placentation. These results are consistent with clinical data suggesting that supraphysiologic estrogen levels seen in IVF pregnancies may play an important role in attenuated trophoblast migration, invasion, and impaired placentation. GATA3 appears to be an important regulator of placentation and may play a role in impaired outcomes associated with fresh IVF cycles.
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Bora
authors.initials: B
authors.lastname: Lee
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California.|UCLA School of Medicine, Los Angeles, California.
authors.forename: Lindsay L
authors.initials: LL
authors.lastname: Kroener
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California.|UCLA School of Medicine, Los Angeles, California.
authors.forename: Erica T
authors.initials: ET
authors.lastname: Wang
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Banks
authors.affiliation: Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Cedars-Sinai-Medical Center, Los Angeles, California.
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.affiliation: Institute for Translational Genomics and Population Sciences, LABiomed/Harbor-UCLA Medical Center, Torrance, California.
authors.forename: Yii-der I
authors.initials: YI
authors.lastname: Chen
authors.affiliation: Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Vineela
authors.initials: V
authors.lastname: Gangalapudi
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California pisarskam@cshs.org.|UCLA School of Medicine, Los Angeles, California.
authors.forename: Margareta D
authors.initials: MD
authors.lastname: Pisarska
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005307:Fertilization in Vitro; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D010920:Placenta / Q000378:metabolism*; D010929:Placentation / Q000502:physiology*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology; D034741:RNA, Small Interfering; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism*
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D034741:RNA, Small Interfering; D011374:Progesterone; D004958:Estradiol
keywords: ART (assisted reproductive technology); GATA3; HTR8/SVneo cells; differential methylation; estrogen regulation; placentation; trophoblast migration