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DNA methylation of intronic enhancers directs tissue-specific expression of steroidogenic factor 1/adrenal 4 binding protein (SF-1/Ad4BP).

Abstract：

: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.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Hoivik EA,Bjanesoy TE,Mai O,Okamoto S,Minokoshi Y,Shima Y,Morohashi K,Boehm U,Bakke M

doi

10.1210/en.2010-1305

subject

Has Abstract

pub_date

2011-05-01 00:00:00

pages

2100-12

issue

eissn

0013-7227

issn

1945-7170

pii

en.2010-1305

journal_volume

152

pub_type

杂志文章

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DNA methylation of intronic enhancers directs tissue-specific expression of steroidogenic factor 1/adrenal 4 binding protein (SF-1/Ad4BP).