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

Lia A Bernardi Wendeln, Matthew T. Dyson, Hideki Tokunaga, Christia Sison, Muge Oral, Jared Cory Robins, Serdar E Bulun*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)60-69
Number of pages10
JournalReproductive Sciences
Volume26
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Endometriosis
Carrier Proteins
Estrogens
Nuclear Receptor Subfamily 6, Group A, Member 1
Stromal Cells
Estradiol
Transcription Factors
Cytoplasmic and Nuclear Receptors
Pregnenolone
Androstenedione
Genes
Progesterone
Proteins
Cholesterol
Phenotype
Messenger RNA

Keywords

  • GATA6
  • NR5A1
  • endometriosis
  • estrogen
  • steroidogenesis

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Bernardi Wendeln, Lia A ; Dyson, Matthew T. ; Tokunaga, Hideki ; Sison, Christia ; Oral, Muge ; Robins, Jared Cory ; Bulun, Serdar E. / The Essential Role of GATA6 in the Activation of Estrogen Synthesis in Endometriosis. In: Reproductive Sciences. 2019 ; Vol. 26, No. 1. pp. 60-69.
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The Essential Role of GATA6 in the Activation of Estrogen Synthesis in Endometriosis. / Bernardi Wendeln, Lia A; Dyson, Matthew T.; Tokunaga, Hideki; Sison, Christia; Oral, Muge; Robins, Jared Cory; Bulun, Serdar E.

In: Reproductive Sciences, Vol. 26, No. 1, 01.01.2019, p. 60-69.

Research output: Contribution to journalArticle

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T1 - The Essential Role of GATA6 in the Activation of Estrogen Synthesis in Endometriosis

AU - Bernardi Wendeln, Lia A

AU - Dyson, Matthew T.

AU - Tokunaga, Hideki

AU - Sison, Christia

AU - Oral, Muge

AU - Robins, Jared Cory

AU - Bulun, Serdar E

PY - 2019/1/1

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N2 - 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.

AB - 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.

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