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GATA-6 Is Expressed in the Human Adrenal and Regulates Transcription of Genes Required for Adrenal Androgen Biosynthesis

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9032

Address all correspondence and requests for reprints to: William E. Rainey, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9032. E-mail: braine{at}mednet.swmed.edu.

Abstract

GATA-6 and GATA-4 are members of a family of transcription factors (GATA 1–6) that share conserved zinc-finger DNA binding domains. Using semiquantitative RT-PCR, we found that the human adrenal expresses mRNA for GATA-6 but not GATA-4. A recent study showed GATA-6 expression in the adrenal reticularis, the source of adrenal androgens. To investigate the role of GATA-6 in regulation of adrenal cell steroidogenesis, luciferase reporter constructs containing the 5'-flanking DNA from steroidogenic acute regulatory protein, cholesterol side-chain cleavage (CYP11A), 17-hydroxylase (CYP17), and dehydroepiandrosterone-sulfotransferase (SULT2A1) were cotransfected with an expression vector containing GATA-6 into adrenal NCI-H295R cells and nonsteroidogenic HEK293 cells. All promoter/reporter constructs were increased by GATA-6 in the adrenal model. However, in the HEK293 cells only SULT2A1 reporter activity was increased by GATA-6. One key difference between H295R and HEK293 cell lines is the differential expression of steroidogenic factor 1 (SF1). Transfection of HEK293 cells with both GATA-6 and SF1 significantly increased transcriptional activation of all reporter constructs above the effect of GATA-6 or SF1 alone. To determine whether the action of GATA-6 required SF1, we transfected HEK293 cells with each promoter construct plus and minus GATA-6, SF1, and/or the orphan nuclear repressor DAX1. DAX1 opposed SF1-activated transcription of many genes and abolished the GATA-6/SF1 ability to increase reporter activity. These results suggest that the adrenal uses GATA-6 to enhance transcription of steroid-metabolizing enzymes needed to produce dehydroepiandrosterone sulfate. Additionally, GATA-6 works in synergy with SF1 to maximally increase expression of enzymes needed to produce adrenal androgens.

IN THE HUMAN adrenal gland, the zona glomerulosa produces aldosterone, the zona fasciculata produces cortisol, and the zona reticularis produces dehyroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S). The mechanisms regulating aldosterone and cortisol production are well-defined; however, the regulation of DHEA and DHEA-S has not yet been fully elucidated. DHEA-S is the most abundant hormone secreted by the human adrenal, and the circulating levels are also high. Steroidogenic acute regulatory protein (StAR), CYP11A, CYP17, and SULT2A1 are needed for the production of DHEA and DHEA-S in the reticularis. However, little is known about the transcriptional regulation of this enzyme in the human adrenal gland.

In the adrenal gland, the genes involved in steroid hormone biosynthesis are regulated by numerous transcription factors. Recent studies have demonstrated that the transcription factor GATA-6 is highly expressed in the adult adrenal zona reticularis, which is the location of DHEA-S biosynthesis (1). A related family member, GATA-4, is expressed in the gonad and plays a prominent role in the transcription of several genes involved in steroid hormone biosynthesis (2, 3, 4, 5, 6, 7). The current study demonstrates that in the adrenal cortex GATA-6 is likely to play a key role in the regulation of expression of the enzymes involved in DHEA-S biosynthesis.

Materials and Methods

Cell culture and transfection assays
HEK293 cells were cultured in DMEM/Ham’s F12 medium (Life Technologies, Inc., Carlsbad, CA) supplemented with 5% NuSerum (Collaborative Bio, Bedford, MA) and antibiotics. Transfection assays were performed using Fugene 6 (Roche, Indianapolis, IN) to transfect 1 µg of reporter plasmid and the indicated amounts of expression vectors. For this article, we selected a strain of H295R cells that grow in DMEM/Ham’s F12 medium supplemented with 10% Cosmic Calf serum (Hyclone, Logan, UT) and antibiotics. In this medium, the cells retained the ability to produce steroid hormones. For transfection experiments, TransFast (Promega, Madison, WI) was used to transfect 1 µg of reporter plasmid and the indicated amounts of expression vectors. pcDNA3.1 zeo empty vector was used to maintain a constant amount of DNA. To normalize luciferase activity, cells were cotransfected with 50 ng/well of ß-gal plasmid (Promega). Cells were assayed 24 h after recovery for activity using the Galacto-Light Plus System (Applied Biosystems, Bedford, MA).

Preparation of reporter constructs and expression vectors
The 5'-flanking DNA from the human StAR, CYP11A, CYP17, and SULT2A1 genes were inserted upstream of the firefly luciferase gene in the reporter vector pGL3 Basic (Promega) as previously described (8). For all transfections, the pGL3 Basic empty vector was used as a control to measure basal activity. The coding regions of human GATA-6 (provided by Dr. Kenneth Walsh, Tufts University), steroidogenic factor 1 (SF1), and DAX1 were inserted into the eukaryotic expression vector pcDNA 3.1 zeo (Invitrogen, Carlsbad, CA).

RNA isolation and semiquantitative RT-PCR
Total RNA was isolated from normal human adrenal tissue obtained from the Cooperative Human Tissue Network (Philadelphia, PA) and ovarian follicles obtained from Parkland Memorial Hospital (Dallas, TX) as described previously (8). The first-strand cDNA synthesis reaction was catalyzed by Superscript II RNase H-reverse transcriptase (Life Technologies, Inc.). The first-strand cDNA synthesis reaction was primed by random hexamers. A semiquantitative method of the relative abundance of GATA-4 and GATA-6 was performed using a procedure previously described (9). Primers for the amplification of the target sequences were based on published sequences for human GATA-4, GATA-6, and glyceraldehyde 3-phosphate dehydrogenase (G3PDH). The sequences used were: GATA-4 (GenBank accession no. NM_002052), forward, 5'-TTGACGACTTCTCAGAAGGC-3', and reverse, 5'-CCAAGACCAGACTGTTCCAA-3'; GATA-6 (GenBank accession no. NM_005257), forward, 5'-GTGAACTGCGGCTCCATCCA-3', and reverse, 5'-CCTTCCCTTCCATCTTCTCTCA-3'; G3PDH (GenBank accession no. AF261085), forward, 5'-CCACCCATGGCAAATTCCATGGCA-3', and reverse, 5'-TCTAGACGGCAGGTCAGGTCCACC-3'. PCR amplification was programmed as follows: denaturing at 94 C for 1 min, annealing at primer-specific temperatures (GATA-4, 50 C; GATA-6, 55 C; G3PDH, 64 C) for 1 min, and extension at 72 C for 1 min. The G3PDH transcript was used as a reference gene to normalize mRNA levels and to evaluate data from the exponential phase of the PCR amplification. PCRs were terminated at various cycle points to decipher the exponential phase of the PCR amplification as indicated in Fig. 1.

View larger version (50K): [in this window] [in a new window]   FIG. 1. Relative mRNA expression patterns of GATA-4 and GATA-6 in human adult adrenal and ovarian follicles determined by semiquantitative RT-PCR was performed using total RNA. GATA-4 was not detected in the adult adrenal but was readily detected in the follicle. GATA-6 mRNA was found in both tissue samples. G3PDH mRNA was used as a reference gene to normalize mRNA levels.

Human steroidogenic tissues express GATA mRNA
Semiquantitative RT-PCR was performed to determine the relative mRNA levels of GATA-4 and GATA-6 in selected human steroidogenic tissues. Total RNA from human adult adrenal and ovarian follicles were used to quantify relative transcript levels of GATA (Fig. 1). Differential expression of GATA-4 was observed with no detectable transcripts in the adrenal and moderate levels in the follicle. Both GATA-4 and GATA-6 transcripts are expressed in ovarian follicles.

GATA-6 increases transcription of the genes involved in steroidogenesis
Because GATA-6 has been localized to the adrenal zona reticularis, we examined its effects on the genes encoding enzymes involved in adrenal androgen production (Fig. 2). Cotransfection of these plasmids with an expression vector containing the coding sequence of GATA-6 in H295R cells resulted in increases in reporter activity of all promoter constructs tested. GATA-6 coexpression increased reporter activity of StAR by 4-fold, CYP11A by 6-fold, CYP17 by 6-fold, and SULT2A1 promoter 7-fold over basal.

View larger version (17K): [in this window] [in a new window]   FIG. 2. A, Effects of GATA-6 on StAR, CYP11A, CYP17, and SULT2A1 transcription in adrenocortical cells. The H295R adrenal cell line was transfected with luciferase promoter constructs (1 µg/well) with or without GATA-6 (0.1 µg/well). B, Effects of GATA-6 on StAR, CYP11A, CYP17, or SULT2A1 transcription in nonsteroidogenic HEK293 cells. Cells were transfected with luciferase promoter constructs (1 µg/well) with or without GATA-6 (0.3 µg/well). Data were normalized to cotransfected ß-gal, and results are expressed as percentage of basal activity. Results are presented as mean ± SEM of data from at least two independent experiments performed in quadruplicate.

GATA-6 synergizes with SF1 to increase transcription of genes involved in steroidogenesis
Cotransfection of nonsteroidogenic HEK293 cells with GATA-6 and SF1 increased luciferase activity of all steroidogenic enzymes tested. The fold increase for each promoter (5- to 54-fold) was significantly higher than increases seen with transfection of SF1 or GATA-6 expression plasmids alone (Fig. 3A). These data indicate a synergistic effect of GATA-6 and SF1 on adrenal steroidogenic enzymes localized in the fasciculata and reticularis.

View larger version (23K): [in this window] [in a new window]   FIG. 3. A, Effects of GATA-6 and SF1 on pGL3 basic, StAR, CYP11A, CYP17, or SULT2A1 transcription. HEK293 cells were transfected with luciferase promoter constructs (1 µg/well) with or without GATA-6 and/or SF1 (0.1 µg/well) expression vectors. B, Effects of DAX1 on GATA-6 and SF1 in StAR, CYP11A, CYP17, or SULT2A1 in nonsteroidogenic cells. Cells were transfected with luciferase promoter constructs with or without GATA-6, SF1, and/or DAX1 (0.1 µg/well) as indicated. Data were normalized to cotransfected ß-gal expression vector, and results are expressed as percentage of basal activity. Results are presented as mean ± SEM of data from a representative experiment of at least two independent experiments performed in triplicate.

Discussion

The C₁₉ adrenal steroids, or the so-called adrenal androgens (DHEA and DHEA-S), are produced at higher levels than either glucocorticoids or mineralocorticoids. However, the mechanisms controlling adrenal production of DHEA and its sulfate remain poorly defined. It is clear that adrenal production of DHEA-S occurs in the zona reticularis of the adrenal cortex and requires expression of StAR, CYP11A, CYP17, and SULT2A1. The expression of these proteins is controlled, to a large degree, at the level of gene transcription. Defining the mechanisms regulating the genes needed to produce DHEA-S could provide important insight into physiological mechanisms regulating adrenal DHEA production. Herein, we demonstrate that the transcription factor GATA-6 is likely a critical determinant of the capacity of the adrenal to produce DHEA-S.

GATA-6 is one of six members of a family of zinc finger transcription factors that regulate target gene transcription through a common DNA sequence, (A/T)GATA(A/G) (10, 11). The six GATA transcription factors can be subdivided into two groups based on expression patterns. GATA1/2/3 are expressed mainly in hematopoietic cells in which they influence differentiation (10). Although structurally similar, GATA4/5/6 are expressed mainly in heart, gut, and gonads (11). Both GATA-4 and -6 appear to be critical for development as supported by the observation that deficient mice die during early development (12, 13). An important role for GATA-4 in gonadal expression of key steroid-synthesizing genes has been suggested by several studies (2, 3, 4, 5, 6, 7). Recent studies have shown that GATA-6 is expressed in the adult human adrenal, where its expression is higher in the reticularis zone of the cortex (1).

The reticularis is known to be the primary producer of DHEA-S within the adrenal cortex. Our study tests the hypothesis that GATA-6 expression in the reticularis influences the capacity to produce adrenal androgens. We demonstrate that in adrenocortical cells GATA-6 was a potent activator of the genes encoding the enzymes needed to produce DHEA-S. Interestingly, the effects of GATA-6 were not reproduced in nonsteroidogenic cells. These data suggest that GATA-6 requires additional proteins that are uniquely expressed in steroidogenic cells to enhance transcription of steroid-metabolizing enzymes.

Several reports on the role of GATA-4 in gonads have suggested that SF1 is needed to maximally induce transcription of gonadal target genes (3, 4, 14, 15). As shown by semiquantitative RT-PCR analysis, the adrenal appears to express only GATA-6. This is unlike the gonad, which expresses both GATA-4 and GATA-6, indicating a unique role for GATA-6 in the adrenal. Therefore, we cotransfected GATA-6 and SF1 into nonsteroidogenic cells and found that GATA-6 and SF1 synergistically stimulated steroidogenic promoter constructs similar to that seen in the adrenocortical model. These data support the concept that within adrenal cells GATA-6 enhancement of target gene activation relies heavily on the presence of SF1. The ability of DAX1 to completely block GATA-6/SF1 activation of StAR, CYP11A, and CYP17 further indicates the need for these proteins to work together. A critical role for GATA-4 interaction with SF1 has also been proposed within the gonads for the transcription of genes encoding steroidogenic enzymes (3, 4) and Müllerian-inhibiting substance (15). In the case of Mullerian inhibiting substance, DAX1 also blocked the GATA-4/SF1 synergy (16).

Whereas SF1 expression is found throughout the adrenal cortex, GATA-6 does appear to be preferentially expressed in the adrenal androgen-producing cells of the reticularis. This adrenocortical distribution of GATA-6 makes this transcription factor an attractive candidate for controlling expression of enzymes needed to produce DHEA-S. The coexpression of both transcription factors in the reticularis should provide the opportunity for cooperative activation of target genes that would increase the capacity to produce DHEA-S.

Footnotes

Abbreviations: DHEA, Dehydroepiandrosterone; DHEA-S, DHEA-sulfate; G3PDH, glyceraldehyde 3-phosphate dehydrogenase; SF1, steroidogenic factor; 1StAR, steroidogenic acute regulatory protein.

Received April 15, 2003.

Accepted for publication July 21, 2003.

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This Article Abstract Full Text (PDF) All Versions of this Article: 144/10/4285    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jimenez, P. Articles by Rainey, W. E. Search for Related Content PubMed PubMed Citation Articles by Jimenez, P. Articles by Rainey, W. E.