The Essential Role of GATA6 in the Activation of Estrogen Synthesis in Endometriosis

Abstract

Endometriotic stromal cells synthesize estradiol via the steroidogenic pathway. Nuclear receptor subfamily 5, group A, member 1 (NR5A1) is critical, but alone not sufficient, in activating this cascade that involves at least 5 genes. To evaluate whether another transcription factor is required for the activation of this pathway, we examined whether GATA Binding Protein 6 (GATA6) can transform a normal endometrial stromal cell (NoEM) into an endometriotic-like cell by conferring an estrogen-producing phenotype. We ectopically expressed GATA6 alone or with NR5A1 in NoEM or silenced these transcription factors in endometriotic stromal cells (OSIS) and assessed the messenger RNAs or proteins encoded by the genes in the steroidogenic cascade. Functionally, we assessed the effects of GATA6 expression or silencing on estradiol formation. In OSIS, GATA6 was necessary for catalyzing the conversion of progesterone to androstenedione (CYP17A1; P < .05). In NoEM, ectopic expression of GATA6 was essential for converting pregnenolone to estrogen (HSD3B2, CYP17A1, and CYP19A1; P < .05). However, simultaneous ectopic expression of both GATA6 and NR5A1 was required and sufficient to confer induction of all 5 genes and their encoded proteins that convert cholesterol to estrogen. Functionally, only simultaneous knockdown of GATA6 and NR5A1 blocked estradiol formation in OSIS ( P < .05). The presence of both transcription factors was required and sufficient to transform endometrial stromal cells into endometriotic-like cells that produced estradiol in large quantities ( P < .05). In summary, GATA6 alone is essential but not sufficient for estrogen formation in endometriosis. However, simultaneous addition of GATA6 and NR5A1 to an endometrial stromal cell is sufficient to transform it into an endometriotic-like cell, manifested by the activation of the estradiol biosynthetic cascade.

Identification and Analyzation of Differentially Expressed Transcription Factors in Endometriosis

“…Another TF, STAT4, was also been linked to endometriosis-related infertility by Zamani et al ( 2016 ). In our research, NR5A1 was high expression in the infertile females with endometriosis and it had the ability to transfer an endometrial stromal cell to an endometriotic-like cell with GATA6 simultaneously by the study of Bernardi et al ( 2019 ). In the meantime, ESR2 also exhibited high expression and studies had proved that ESR2 could influence susceptibility to endometriosis with infertility (Lamp et al, 2011 ).…”

Current Knowledge on Endometriosis Etiology: A Systematic Review of Literature

“… 34 DNMT-3B aberrantly expressed itself inside eutopic endometrial and endometriotic stromal cells during decidualization, linking to genetic areas of the steroidogenic factor 1 ( NR5A ) and estrogen alpha-receptor ( ESR1 ). 35 , 36 Also, abnormal DNA methylation in endometriosis activates the expression of several genes, including homeobox A10 ( HOXA10 ), estrogen beta-receptor gene ( ESR2 ), progesterone receptor (PGR), aromatase ( CYP19A1, HOXC6 , and ALDH1A2) ( Figure 1 ). 23 , 31 , 37 , 38

Figure 1 Schematic representation of epigenetic changes associated with endometriosis.

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Integrated Bioinformatics Analysis Reveals Function and Regulatory Network of miR-200b-3p in Endometriosis

“…A total of 110 target genes of miR-200b-3p were screened, and many of them play important roles in the development of endometriosis. They included FOXP1, GATA6, JUN, and EGFR involved in muscle cell proliferation [25][26][27][28]; NTRK2, ZFPM, and VEGFA involved in angiogenesis [29,30]; and DNMT1, EZH2, FOXP1, VEGFA, ZEB1, and ZEB2 involved in EMT [31,32]. Recent studies found that EMT plays an important role in the occurrence and development of endometriosis [33].…”