Two-Step Regulation of Ad4BP/SF-1 Gene Transcription during Fetal Adrenal Development: Initiation by a Hox-Pbx1-Prep1 Complex and Maintenance via Autoregulation by Ad4BP/SF-1

ABSTRACT The orphan nuclear receptor Ad4BP/SF-1 (adrenal 4 binding protein/steroidogenic factor 1) is essential for the proper development and function of reproductive and steroidogenic tissues. Although the expression of Ad4BP/SF-1 is specific for those tissues, the mechanisms underlying this tissue-specific expression remain unknown. In this study, we used transgenic mouse assays to examine the regulation of the tissue-specific expression of Ad4BP/SF-1. An investigation of the entire Ad4BP/SF-1 gene locus revealed a fetal adrenal enhancer (FAdE) in intron 4 containing highly conserved binding sites for Pbx-Prep, Pbx-Hox, and Ad4BP/SF-1. Transgenic assays revealed that the Ad4 sites, together with Ad4BP/SF-1, develop an autoregulatory loop and thereby maintain transcription, while the Pbx/Prep and Pbx/Hox sites initiate transcription prior to the establishment of the autoregulatory loop. Indeed, a limited number of Hox family members were found to be expressed in the adrenal primordia. Whether a true fetal-type adrenal cortex is present in mice remained controversial, and this argument was complicated by the postnatal development of the so-called X zone. Using transgenic mice with lacZ driven by the FAdE, we clearly identified a fetal adrenal cortex in mice, and the X zone is the fetal adrenal cells accumulated at the juxtamedullary region after birth.

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Structure and function of the chromogranin A gene. Clues to evolution and tissue-specific expression

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)98814-9 ◽

1991 ◽

Vol 266 (20) ◽

pp. 13130-13134

Author(s):

H.J. Wu ◽

D.J. Rozansky ◽

R.J. Parmer ◽

B.M. Gill ◽

D.T. O'Connor

Keyword(s):

Chromogranin A ◽

Structure And Function ◽

Specific Expression ◽

Tissue Specific ◽

Tissue Specific Expression ◽

And Function

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Characterization of the human SLC2A11 (GLUT11) gene: alternative promoter usage and splicing, tissue-specific expression, and function of three isoforms

10.1240/sav_gbm_2005_h_001323 ◽

2005 ◽

Vol 2005 (Fall) ◽

Author(s):

Andrea Scheepers ◽

Stefan Schmidt ◽

Chris I. Cheeseman ◽

Hans-Georg Joost ◽

Annette Schürmann

Keyword(s):

Alternative Promoter ◽

Specific Expression ◽

Tissue Specific ◽

Tissue Specific Expression ◽

Promoter Usage ◽

And Function

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Role of DNA methylation in the tissue-specific expression of the CYP17A1 gene for steroidogenesis in rodents

Journal of Endocrinology ◽

10.1677/joe-08-0353 ◽

2009 ◽

Vol 202 (1) ◽

pp. 99-109 ◽

Cited By ~ 43

Author(s):

Elika Missaghian ◽

Petra Kempná ◽

Bernhard Dick ◽

Andrea Hirsch ◽

Rasoul Alikhani-Koupaei ◽

...

Keyword(s):

Dna Methylation ◽

Histone Deacetylase Inhibitors ◽

Cpg Island ◽

Specific Expression ◽

Tissue Specific ◽

Adrenal Cells ◽

Tissue Specific Expression ◽

As Species ◽

Species Specific

The CYP17A1 gene is the qualitative regulator of steroidogenesis. Depending on the presence or absence of CYP17 activities mineralocorticoids, glucocorticoids or adrenal androgens are produced. The expression of the CYP17A1 gene is tissue as well as species-specific. In contrast to humans, adrenals of rodents do not express the CYP17A1 gene and have therefore no P450c17 enzyme for cortisol production, but produce corticosterone. DNA methylation is involved in the tissue-specific silencing of the CYP17A1 gene in human placental JEG-3 cells. We investigated the role of DNA methylation for the tissue-specific expression of the CYP17A1 gene in rodents. Rats treated with the methyltransferase inhibitor 5-aza-deoxycytidine excreted the cortisol metabolite tetrahydrocortisol in their urine suggesting that treatment induced CYP17 expression and 17α-hydroxylase activity through demethylation. Accordingly, bisulfite modification experiments identified a methylated CpG island in the CYP17 promoter in DNA extracted from rat adrenals but not from testes. Both methyltransferase and histone deacetylase inhibitors induced the expression of the CYP17A1 gene in mouse adrenocortical Y1 cells which normally do not express CYP17, indicating that the expression of the mouse CYP17A1 gene is epigenetically controlled. The role of DNA methylation for CYP17 expression was further underlined by the finding that a reporter construct driven by the mouse −1041 bp CYP17 promoter was active in Y1 cells, thus excluding the lack of essential transcription factors for CYP17 expression in these adrenal cells.

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DNA Methylation of Intronic Enhancers Directs Tissue-Specific Expression of Steroidogenic Factor 1/Adrenal 4 Binding Protein (SF-1/Ad4BP)

Endocrinology ◽

10.1210/en.2010-1305 ◽

2011 ◽

Vol 152 (5) ◽

pp. 2100-2112 ◽

Cited By ~ 41

Author(s):

Erling A. Hoivik ◽

Trine E. Bjanesoy ◽

Oliver Mai ◽

Shiki Okamoto ◽

Yasuhiko Minokoshi ◽

...

Keyword(s):

Dna Methylation ◽

Binding Protein ◽

Methylation Status ◽

Hypothalamic Nucleus ◽

Dependent Manner ◽

Specific Expression ◽

Steroidogenic Factor 1 ◽

Tissue Specific ◽

Tissue Specific Expression ◽

Ventromedial Hypothalamic Nucleus

The nuclear receptor steroidogenic factor 1/adrenal 4 binding protein (SF-1/Ad4BP) is an essential regulator of endocrine development and function, and the expression of the corresponding gene (sf-1/ad4bp) is precisely regulated in a time- and tissue-dependent manner. We previously demonstrated that the basal promoter of sf-1/ad4bp is controlled by DNA methylation and that its methylation status reflects the expression pattern of SF-1/Ad4BP. Recently, three intronic enhancers were identified in the sf-1/ad4bp gene that target SF-1/Ad4BP expression to the fetal adrenal (FAdE; fetal adrenal-specific enhancer), to pituitary gonadotropes (PGE; pituitary gonadotrope-specific enhancer), and to the ventromedial hypothalamic nucleus (VMHE; ventromedial hypothalamic nucleus-specific enhancer). Here, we demonstrate that the activity of these enhancers is correlated with their DNA methylation status. We show that they are hypomethylated in tissues where they are active and generally hypermethylated in tissues where they are not active. Furthermore, we demonstrate in transient transfection experiments that forced DNA methylation represses reporter gene activity driven by these enhancers. These data directly demonstrate a functional significance for the enhancers' methylation status. Intriguingly, further analyses of the basal promoter in gonadotropes revealed that it is methylated in these cells, in contrast to other SF-1/Ad4BP-expressing tissues. Consistent with this, sf-1/ad4bp is transcribed from an alternative promoter in gonadotropes. Taken together, our experiments show that the tissue-specific expression of SF-1/Ad4BP is epigenetically regulated and identify tissue-specific differentially methylated regions within the sf-1/ad4bp locus that are essential for its transcriptional control.

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