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

Lia A Bernardi, Matthew T Dyson, Hideki Tokunaga, Christia Sison, Muge Oral, Jared C Robins, Serdar E Bulun
Reproductive sciences (Thousand Oaks, Calif.) · 2018 · vol. 26(1) , pp. 60–69 · doi:10.1177/1933719118756751 · PMID:29402198 · W2789894649
article OA: bronze CC0 ⤵ 29 in-corpus citations
📄 Open PDF Full text JSON View on OpenAlex View on PubMed View at publisher
⚙ AI-generated summary by claude@2026-06+body, 2026-06-08 ⓘ

GATA6 is essential for estrogen synthesis in endometriosis, and its co-expression with NR5A1 transforms endometrial cells into estradiol-producing endometriotic-like cells.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

Full text 7,567 characters · extracted from oa-doi-fallback · 2 sections · click to expand

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. Similar content being viewed by others

References

Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364(9447): 1789–1799. Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3(2):93–110.43. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268–279. Bulun SE, Lin Z, Imir G, et al. Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev. 2005;57(3):359–383. Lavoie HA, King SR. Transcriptional regulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B. Exp Biol Med. 2009; 234(8):880–907. Xue Q, Lin Z, Yin P, et al. Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5’ CpG island in endometriosis. J Clin Endocrinol Metab. 2007;92(8): 3261–3267. Dyson MT, Roqueiro D, Monsivais D, et al. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet. 2014;10(3):e1004158. Schimmer BP, White PC. Minireview: steroidogenic factor 1: its roles in differentiation, development, and disease. Mol Endocrinol. 2010;24(7):1322–1337. Lala DS, Rice DA, Parker KL. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol Endocrinol. 1992;6(8): 1249–1258. Sugawara T, Holt JA, Kiriakidou M, Strauss JF III. Steroidogenic factor 1-dependent promoter activity of the human steroidogenic acute regulatory protein (StAR) gene. Biochemistry. 1996;35(28): 9052–9059. Parker KL, Rice DA, Lala DS, et al. Steroidogenic factor 1: an essential mediator of endocrine development. Recent Prog Horm Res. 2002;57:19–36. Vasquez YM, Wu SP, Anderson ML, et al. Endometrial expression of steroidogenic factor 1 promotes cystic glandular morphogenesis. Mol Endocrinol. 2016;30(5):518–532. Tremblay JJ, Viger RS. Novel roles for GATA transcription factors in the regulation of steroidogenesis. J Steroid Biochem Mol Biol. 2003;85(2-5):291–298. Viger RS, Guittot SM, Anttonen M, Wilson DB, Heikinheimo M. Role of the GATA family of transcription factors in endocrine development, function, and disease. Mol Endocrinol. 2008;22(4): 781–798. Zaret KS, Carroll JS. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 2011;25(21): 2227–2241. Shu J, Zhang K, Zhang M, et al. GATA family members as inducers for cellular reprogramming to pluripotency. Cell Res. 2015;25(2):169–180. Orkin SH. GATA-binding transcription factors in hematopoietic cells. Blood. 1992;80(3):575–581. Molkentin JD. The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem. 2000;275(50): 38949–38952. Convissar SM, Bennett J, Baumgarten SC, Lydon JP, DeMayo FJ, Stocco C. GATA4 and GATA6 knockdown during luteinization inhibits progesterone production and gonadotropin responsiveness in the corpus luteum of female mice. Biol Reprod. 2015; 93(6):133. Jimenez P, Saner K, Mayhew B, Rainey WE. GATA-6 is expressed in the human adrenal and regulates transcription of genes required for adrenal androgen biosynthesis. Endocrinology. 2003;144(10):4285–4288. Martin LJ, Taniguchi H, Robert NM, Simard J, Tremblay JJ, Viger RS. GATA factors and the nuclear receptors, steroido-genic factor 1/liver receptor homolog 1, are key mutual partners in the regulation of the human 3beta-hydroxysteroid dehydro-genase type 2 promoter. Mol Endocrinol. 2005;19(9): 2358–2370. Fluck CE, Miller WL. GATA-4 and GATA-6 modulate tissue-specific transcription of the human gene for P450c17 by direct interaction with Sp1. Mol Endocrinol. 2004;18(5): 1144–1157. Tremblay JJ, Viger RS. Transcription factor GATA-4 enhances Mullerian inhibiting substance gene transcription through a direct interaction with the nuclear receptor SF-1. Mol Endocrinol. 1999; 13(8):1388–1401. Noble LS, Takayama K, Zeitoun KM, et al. Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells. J Clin Endocrinol Metab. 1997;82(2):600–606. Ryan IP, Schriock ED, Taylor RN. Isolation, characterization, and comparison of human endometrial and endometriosis cells in vitro. J Clin Endocrinol Metab. 1994;78(3):642–649. Monsivais D, Dyson MT, Yin P, et al. ERbeta- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis. Mol Endocrinol. 2014;28(8):1304–1315. Dyson MT, Kowalewski MP, Manna PR, Stocco DM. The differential regulation of steroidogenic acute regulatory protein-mediated steroidogenesis by type I and type II PKA in MA-10 cells. Mol Cell Endocrinol. 2009;300(1-2):94–103. Dyson MT, Jones JK, Kowalewski MP, et al. Mitochondrial A-kinase anchoring protein 121 binds type II protein kinase A and enhances steroidogenic acute regulatory protein-mediated steroidogenesis in MA-10 mouse leydig tumor cells. Biol Reprod. 2008;78(2):267–277. Attar E, Tokunaga H, Imir G, et al. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab. 2009;94(2): 623–631. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Bernardi, L.A., Dyson, M.T., Tokunaga, H. et al. The Essential Role of GATA6 in the Activation of Estrogen Synthesis in Endometriosis. Reprod. Sci. 26, 60–69 (2019). https://doi.org/10.1177/1933719118756751 Published: Version of record: Issue date: DOI: https://doi.org/10.1177/1933719118756751

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

⚙ Ask this paper AI returns verbatim quotes from the full text · source: oa-doi-fallback ⓘ

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Condition tags

mesh:D004715endometriosis

MeSH descriptors

Endometriosis Estradiol GATA6 Transcription Factor Steroidogenic Factor 1 Adult Cells, Cultured Endometriosis Endometrium Endometrium Estradiol Female GATA6 Transcription Factor Humans Steroidogenic Factor 1 Stromal Cells Stromal Cells

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (33)

Cited by (29)

Source provenance

europepmc
last seen: 2026-06-04T01:30:01.192114+00:00
openalex
last seen: 2026-06-04T00:00:01.174412+00:00
pubmed
last seen: 2026-05-13T22:20:01.354358+00:00
License: CC0 · commercial use OK