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.

Abnormal Placentation Associated with Infertility as a Marker of Overall Health

“…Conditions leading to infertility may be involved with abnormal placentation and trophoblast invasion. 22,74,75 The etiology of recurrent pregnancy loss may also come back to the trophoblast. Premature loosening of trophoblast connections and consequent premature and disorganized flow of maternal blood into the intervillous space have been associated with recurrent spontaneous abortion.…”

Does Estradiol Orally and Vaginally Administered Together Impact Live Birth and Neonatal Outcome in Artificial Frozen-thawed Embryo Transfer Cycles: A Retrospective Cohort Study

“…Adverse perinatal outcomes such as low birth weight newborn in term singletons have been associated with fresh IVF-ET because of the hyperestrogenic milieu generated during COS in IVF [7][8][9][10][11]. Excessive E2 priming induced from development and recruitment of multiple follicles can affect gene expression pattern change like Grb10 and GATA3, and generate epigenetic alterations in developing embryo and fetus through alterations in DNA methylation, histone alteration and others [27][28][29][30]. It is also reported that immune environment changed due to the increase of natural killer cells in oocytes during stimulated cycles compared with natural cycles [31].…”

Effects of oestradiol for luteal phase support in fresh embryo transfer cycles: A retrospective cohort study

“…Giorgetti et al found that PAPP‐A protein level was strongly negatively correlated with oestrogen level on the hCG day and that it played a key role in the invasion of trophoblast cells by increasing the tolerance of the intima to the foetus . In addition, a recent study showed that high oestrogen levels affect the expression of GATA3 in trophoblast cells, thereby affecting their migration, invasion and cultivation . Therefore, persistently high oestrogen levels during early pregnancy should be avoided in luteal support.…”

“…34 In addition, a recent study showed that high oestrogen levels affect the expression of GATA3 in trophoblast cells, thereby affecting their migration, invasion and cultivation. 35 Therefore, persistently high oestrogen levels during early pregnancy should be avoided in luteal support.…”