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

Endocrinology ◽  
2011 ◽  
Vol 152 (5) ◽  
pp. 2100-2112 ◽  
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.

scholarly journals 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

2006 ◽  
Vol 26 (11) ◽  
pp. 4111-4121 ◽  
Author(s):  
Mohamad Zubair ◽  
Satoru Ishihara ◽  
Sanae Oka ◽  
Katsuzumi Okumura ◽  
Ken-ichirou Morohashi
Keyword(s):  
Adrenal Cortex ◽  
Binding Sites ◽  
Orphan Nuclear Receptor ◽  
Specific Expression ◽  
Steroidogenic Factor 1 ◽  
Tissue Specific ◽  
Adrenal Cells ◽  
Tissue Specific Expression ◽  
And Function ◽  
Intron 4

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.

scholarly journals DNA Methylation of Alternative Promoters Directs Tissue Specific Expression of Epac2 Isoforms

PLoS ONE ◽  
2013 ◽  
Vol 8 (7) ◽  
pp. e67925 ◽  
Author(s):  
Erling A. Hoivik ◽  
Solveig L. Witsoe ◽  
Inger R. Bergheim ◽  
Yunjian Xu ◽  
Ida Jakobsson ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Alternative Promoters ◽  
Specific Expression ◽  
Tissue Specific ◽  
Tissue Specific Expression

scholarly journals Deoxyribonucleic Acid Methylation Controls Cell Type-Specific Expression of Steroidogenic Factor 1

Endocrinology ◽  
2008 ◽  
Vol 149 (11) ◽  
pp. 5599-5609 ◽  
Author(s):  
Erling A. Hoivik ◽  
Linda Aumo ◽  
Reidun Aesoy ◽  
Haldis Lillefosse ◽  
Aurélia E. Lewis ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Rna Polymerase Ii ◽  
Methylation Status ◽  
Endocrine System ◽  
Methylation Pattern ◽  
Proximal Promoter ◽  
Specific Expression ◽  
Steroidogenic Factor 1 ◽  
In Cells

Steroidogenic factor 1 (SF1) is expressed in a time- and cell-specific manner in the endocrine system. In this study we present evidence to support that methylation of CpG sites located in the proximal promoter of the gene encoding SF1 contributes to the restricted expression pattern of this nuclear receptor. DNA methylation analyses revealed a nearly perfect correlation between the methylation status of the proximal promoter and protein expression, such that it was hypomethylated in cells that express SF1 but hypermethylated in nonexpressing cells. Moreover, in vitro methylation of this region completely repressed reporter gene activity in transfected steroidogenic cells. Bisulfite sequencing of DNA from embryonic tissue demonstrated that the proximal promoter was unmethylated in the developing testis and ovary, whereas it was hypermethylated in tissues that do not express SF1. Together these results indicate that the DNA methylation pattern is established early in the embryo and stably inherited thereafter throughout development to confine SF1 expression to the appropriate tissues. Chromatin immunoprecipitation analyses revealed that the transcriptional activator upstream stimulatory factor 2 and RNA polymerase II were specifically recruited to this DNA region in cells in which the proximal promoter is hypomethylated, providing functional support for the fact that lack of methylation corresponds to a transcriptionally active gene. In conclusion, we identified a region within the SF1/Sf1 gene that epigenetically directs cell-specific expression of SF1.

scholarly journals Bridging sequence diversity and tissue-specific expression by DNA methylation in genes of the mouse prolactin superfamily

2011 ◽  
Vol 23 (5-6) ◽  
pp. 336-345 ◽  
Author(s):  
Koji Hayakawa ◽  
Momo O. Nakanishi ◽  
Jun Ohgane ◽  
Satoshi Tanaka ◽  
Mitsuko Hirosawa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Sequence Diversity ◽  
Specific Expression ◽  
Tissue Specific ◽  
Tissue Specific Expression

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

2009 ◽  
Vol 202 (1) ◽  
pp. 99-109 ◽  
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.

scholarly journals Hypermethylation of human DNA: Fine-tuning transcription associated with development

2017 ◽  
Author(s):  
Carl Baribault ◽  
Kenneth C. Ehrlich ◽  
V. K. Chaithanya Ponnaluri ◽  
Sriharsa Pradhan ◽  
Michelle Lacey ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Regulatory Elements ◽  
Fine Tuning ◽  
Ctcf Binding ◽  
Specific Gene ◽  
Dna Hypermethylation ◽  
Specific Expression ◽  
Lncrna Gene ◽  
Tissue Specific ◽  
Tissue Specific Expression

AbstractTissue-specific gene transcription can be affected by DNA methylation in ways that are difficult to discern from studies focused on genome-wide analyses of differentially methylated regions (DMRs). We studied 95 genes in detail using available epigenetic and transcription databases to detect and elucidate less obvious associations between development-linked hypermethylated DMRs in myoblasts (Mb) and cell-and tissue-specific expression. Many of these genes encode developmental transcription factors and display DNA hypermethylation also in skeletal muscle (SkM) and a few heterologous samples (e.g., aorta, mammary epithelial cells, or brain) among the 38 types of human cell cultures or tissues examined. Most of the DMRs overlapped transcription regulatory elements, including canonical, alternative, or cryptic promoters; enhancers; CTCF binding sites; and long-noncoding RNA (lncRNA) gene regions. Among the prominent relationships between DMRs and expression was promoter-region hypermethylation accompanying repression in Mb but not in many other repressed samples (26 genes). Another surprising relationship was down-modulated (but not silenced) expression in Mb associated with DNA hypermethylation at cryptic enhancers in Mb although such methylation was absent in both non-expressing samples and highly expressing samples (24 genes). The tissue-specificity of DNA hypermethylation can be explained for many of the genes by their roles in prenatal development or by the tissue-specific expression of neighboring genes. Besides elucidating developmental epigenetics, our study provides insights into the roles of abnormal DNA methylation in disease, e.g., cancer, Duchenne muscular dystrophy, and congenital heart malformations.

scholarly journals DNA methylation regulates tissue-specific expression of Shank3

2007 ◽  
Vol 101 (5) ◽  
pp. 1380-1391 ◽  
Author(s):  
Silvana Beri ◽  
Noemi Tonna ◽  
Giorgia Menozzi ◽  
Maria Clara Bonaglia ◽  
Carlo Sala ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Specific Expression ◽  
Tissue Specific ◽  
Tissue Specific Expression
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