Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia.
Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia.
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DOI：
10.1038/s41598-017-11435-2
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发表时间：
2017-09-11
影响因子：
4.6
通讯作者：
Takeda Y
中科院分区：
文献类型：
--
作者：
Kometani M;Yoneda T;Demura M;Koide H;Nishimoto K;Mukai K;Gomez-Sanchez CE;Akagi T;Yokota T;Horike SI;Karashima S;Miyamori I;Yamagishi M;Takeda Y
原发性醛固酮增多症（PA）或高皮质醇血症导致肾上腺皮质激素过量，导致高血压和心血管并发症。在PA中，醛固酮合成酶（CYP11B2）的低甲基化与醛固酮过量产生有关。然而，在高皮质醇血症中，催化皮质醇生物合成且与CYP11B2高度同源的11β-羟化酶（CYP11B1） DNA甲基化的作用尚不清楚。我们的研究目的是确定高皮质醇血症伴皮质醇生成腺瘤（CPA）中CYP11B1的表达是否通过DNA甲基化调节，并探讨DNA甲基化与CPA中发现的体细胞突变之间的可能关系。甲基化分析显示，CYP11B1启动子在CPA中的甲基化程度明显低于邻近未受影响的肾上腺组织和白细胞。此外，在蛋白激酶A （PRKACA）催化亚基或鸟嘌呤核苷酸结合蛋白亚基α (GNAS)基因发生体细胞突变的CPA中，CYP11B1启动子显著低甲基化。此外，DNA甲基化降低了CYP11B1启动子活性。我们的研究结果表明，CYP11B1启动子的DNA甲基化在CPA中调节CYP11B1的表达和皮质醇的产生中起作用，并且与CPA相关的体细胞突变减少了CYP11B1启动子的DNA甲基化。
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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影响因子：
2.7
作者：
Cheng, Li-Chuan;Pai, Tun-Wen;Li, Lih-Ann
通讯作者：
Li, Lih-Ann
影响因子：
5.8
作者：
Nishimoto, Koshiro;Nakagawa, Ken;Mukai, Kuniaki
通讯作者：
Mukai, Kuniaki
影响因子：
30.8
作者：
Goh, Gerald;Scholl, Ute I.;Healy, James M.;Choi, Murim;Prasad, Manju L.;Nelson-Williams, Carol;Kuntsman, John W.;Korah, Reju;Suttorp, Anna-Carinna;Dietrich, Dimo;Haase, Matthias;Willenberg, Holger S.;Stalberg, Peter;Hellman, Per;Akerstrom, Goran;Bjorklund, Peyman;Carling, Tobias;Lifton, Richard P.
通讯作者：
Lifton, Richard P.
DOI：
10.1161/hypertensionaha.116.08313
发表时间：
2016-12
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Yoshii Y;Oki K;Gomez-Sanchez CE;Ohno H;Itcho K;Kobuke K;Yoneda M
通讯作者：
Yoneda M
影响因子：
4.5
作者：
Feldmann A;Ivanek R;Murr R;Gaidatzis D;Burger L;Schübeler D
通讯作者：
Schübeler D