Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-09-11

AUTHORS

Mitsuhiro Kometani, Takashi Yoneda, Masashi Demura, Hiroshi Koide, Koshiro Nishimoto, Kuniaki Mukai, Celso E. Gomez-Sanchez, Tadayuki Akagi, Takashi Yokota, Shin-ichi Horike, Shigehiro Karashima, Isamu Miyamori, Masakazu Yamagishi, Yoshiyu Takeda

ABSTRACT

Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter. More... »

PAGES

11205

Journal

TITLE

Scientific Reports

ISSUE

1

VOLUME

7

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-11435-2

DOI

http://dx.doi.org/10.1038/s41598-017-11435-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1091547599

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28894201


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27 schema:description Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter.
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35 CYP11B2
36 DNA methylation
37 activity
38 addition
39 adenomas
40 adrenal tissue
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42 aldosterone overproduction
43 aldosterone synthase
44 aldosteronism
45 alpha gene
46 analysis
47 biosynthesis
48 blood cells
49 cardiovascular complications
50 catalytic subunit
51 cells
52 complications
53 cortisol biosynthesis
54 cortisol overproduction
55 cortisol production
56 cortisol-producing adenomas
57 excess
58 expression
59 genes
60 guanine
61 hormone excess
62 hypercortisolemia
63 hypertension
64 hypomethylation
65 kinase A
66 methylation
67 methylation analysis
68 mutations
69 overproduction
70 possible relationship
71 primary aldosteronism
72 production
73 promoter
74 promoter activity
75 protein kinase A
76 regulation
77 relationship
78 reporter
79 results
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81 somatic mutations
82 study
83 study results
84 subunits
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86 tissue
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