Methylation of a conserved intronic CpG island of mouse SF-1 is associated with cell-specific expression of SF-1 in a culture system but not with tissue-specific expression

Shirohzu, Hisao; Okabe, Taijiro; Gondo, Shigeki; Tanaka, Tomoko; Ohe, Kenji; Morinaga, Hidetaka; Kawate, Hisaya; Nomura, Masatoshi; Takayanagi, Ryoichi; Nawata, Hajime; Yanase, Toshihiko

doi:10.1016/j.bbrc.2008.02.110

Cited by 6 publications

(3 citation statements)

References 22 publications

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“…We paid a special attention to the role of DNA methylation at the NR5A1 and GIPR loci that were distinct in subtype 1 and two other subtypes of somatotroph tumors. Epigenetic, DNA methylation-related regulation of NR5A1 was previously described in various cell types expressing SF-1 [29,30,39,40]. NR5A1 encodes SF-1 transcription factor, which serves as a diagnostic marker of pituitary tumors of gonadotrophic lineage origin, but the expression of this gene in a subset of somatotroph tumors has been already reported by independent groups [9][10][11][12][13][14][15][16][17].…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Pattern in Somatotroph Pituitary Neuroendocrine Tumors

Kober,

Rymuza,

Baluszek

et al. 2023

Neuroendocrinology

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Introduction: Growth hormone secretion by sporadic somatotroph neuroendocrine pituitary tumors (PitNETs) is a major cause of acromegaly. These tumors are relatively heterogenous in terms of histopathological and molecular features. Our previous transcriptomic profiling of somatotroph tumors revealed three distinct molecular subtypes. This study aimed to investigate the difference in DNA methylation patterns in subtypes of somatotroph PitNETs and its role in distinctive gene expression. Methods: Genome-wide DNA methylation was investigated in 48 somatotroph PitNETs with EPIC microarrays. Gene expression was assessed with RNAseq. Bisulfite pyrosequencing and qRT-PCR were used for verifying the results of DNA methylation and gene expression. Results: Clustering tumor samples based on methylation data reflected the transcriptome-related classification. Subtype 1 tumors are densely granulated without GNAS mutation, characterized by high expression of NR5A1 (SF-1) and GIPR. The expression of both genes is correlated with specific methylation of the gene body and promoter. This subtype has a lower methylation level of 5′ gene regions and CpG islands than the remaining tumors. Subtype 2 PitNETs are densely granulated and frequently GNAS-mutated, while those in subtype 3 are mainly sparsely granulated. Methylation/expression analysis indicates that ∼50% genes located in differentially methylated regions are those differentially expressed between tumor subtypes. Correlation analysis revealed DNA methylation-controlled genes, including CDKN1B, CCND2, EBF3, CDH4, CDH12, MGMT, STAT5A, PLXND1, PTPRE, and MMP16, and genes encoding ion channels and semaphorins. Conclusion: DNA methylation profiling confirmed the existence of three molecular subtypes of somatotroph PitNETs. High expression of NR5A1 and GIPR in subtype 1 tumors is correlated with specific methylation of both genes.

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Section: Discussionmentioning

confidence: 99%

DNA Methylation Pattern in Somatotroph Pituitary Neuroendocrine Tumors

Kober,

Rymuza,

Baluszek

et al. 2023

Neuroendocrinology

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Section: Discussionmentioning

confidence: 99%

“…25 Shirohzu et al demonstrated that the upstream intron 1 CpG island sequence of mouse SF-1 was differentially methylated between an in vitro mouse cell culture system and normal mouse tissues; moreover, hypermethylation of this intron region activated SF-1 mRNA expression in adrenocortical Y-1 cells, but the methylation status of this region did not predominantly affect the tissue-or development-specific expression patterns of SF-1. 26 To gain further insights into the mechanisms that underlie the confined activity of the intronic enhancers and thus the tissuespecific expression of the SF-1 locus, we applied the CpGPlot identification analysis to the human SF-1 intron region ( Figure 1A) and found a novel downstream CpG island around intron 1. Our data showed that the methylation status between the þ3462 bp and þ3633 bp regions of the SF-1 gene was positively associated with mRNA levels in endometriotic cells.…”

Section: Discussionmentioning

confidence: 99%

Methylation of a Novel CpG Island of Intron I Is Associated With Steroidogenic Factor I Expression in Endometriotic Stromal Cells

Xue

Yang

et al. 2014

Reprod. Sci.

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Steroidogenic factor 1 (SF-1), a transcriptional factor essential for estrogen biosynthesis, is undetectable in endometrial stromal cells and aberrantly expressed in endometriotic stromal cells. Objective: We tried to gain further insight into the mechanism for differential SF-1 expression in endometrial and endometriotic stromal cells. Design: We had previously identified a novel CpG island in SF-1, which is located in the downstream intron 1 region. Here, we evaluated the methylation status of this CpG island. Patients: We obtained the eutopic endometrium from disease-free participants (n ¼ 8) and the walls of cystic endometriosis lesions of the ovaries from another group of participants (n ¼ 8). None of the patients had received any preoperative hormonal therapy. Interventions: Stromal cells were isolated from these 2 types of tissues and subjected to DNA bisulfite treatment and sequence analysis. Results: The SF-1 messenger RNA (mRNA) levels in endometriotic stromal cells were significantly higher than those in endometrial stromal cells. Bisulfite sequencing showed strikingly increased methylation of a 1-kbp region around the previously identified CpG island in endometriotic cells compared with endometrial cells (P < .001). A strong correlation between SF-1 mRNA levels and percentage methylation of the intron 1 region of the SF-1 gene was observed in endometriotic cells (Spearman correlation coefficient, .96; P < .001). Conclusions: Methylation of the intron 1 region of the SF-1 gene is associated with its expression in endometriotic cells. This CpG island therefore plays an important role in regulating SF-1 expression.

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