Dynamic CCAAT/enhancer binding protein-associated changes of DNA methylation in the angiotensinogen gene

Fen Wang, Masashi Demura, Yuan Cheng, Aoshuang Zhu, Shigehiro Karashima, Takashi Yoneda, Yoshiki Demura, Yuji Maeda, Mikio Namiki, Katsuhiko Ono, Yasuhiro Nakamura, Hironobu Sasano, Tadayuki Akagi, Masakazu Yamagishi, Kiyofumi Saijoh, Yoshiyu Takeda

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

DNA methylation patterns are maintained in adult somatic cells. Recent findings, however, suggest that all methylation patterns are not preserved. We demonstrate that stimulatory signals can change the DNA methylation status at a CCAAT/enhancer binding protein (CEBP) binding site and a transcription start site and activate expression of the angiotensinogen gene (AGT). A CEBP binding site in the human AGT promoter was hypomethylated in tissues with high expression of AGT, but not in those with low expression. The transcriptional activity of AGT promoter sequences cloned into a reporter plasmid depended on DNA methylation. In cultured human cells, interleukin 6 stimulation caused DNA demethylation around a CEBP binding site and a transcription start site; demethylation was accompanied by increased CEBP-β recruitment and chromatin accessibility of the AGT promoter. DNA methylation activity decreased in the nucleus. Excess circulating aldosterone upregulated AGT expression and was accompanied by DNA hypomethylation around a CEBP binding site and a transcription start site in human visceral adipose tissue. High salt intake led to upregulation of Agt expression, DNA hypomethylation around 2 CEBP binding sites and a transcription start site, and decreased DNA methylation activity in rat visceral adipose tissue. Taken together, CEBP binding initiates chromatin relaxation and transcription, which are followed by DNA demethylation around a CEBP binding site and a transcription start site in the AGT promoter. Decreased DNA methylation activity in the nucleus may play a role in DNA demethylation. DNA demethylation switches the phenotype of AGT expression from an inactive to an active state.

Original languageEnglish
Pages (from-to)281-288
Number of pages8
JournalHypertension
Volume63
Issue number2
DOIs
Publication statusPublished - 2014 Feb

Keywords

  • CCAAT-enhancer binding protein-ß
  • CEBPB protein
  • DNA methylation
  • angiotensinogen
  • chromatin
  • human
  • transcription initiation site

ASJC Scopus subject areas

  • Internal Medicine

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  • Cite this

    Wang, F., Demura, M., Cheng, Y., Zhu, A., Karashima, S., Yoneda, T., Demura, Y., Maeda, Y., Namiki, M., Ono, K., Nakamura, Y., Sasano, H., Akagi, T., Yamagishi, M., Saijoh, K., & Takeda, Y. (2014). Dynamic CCAAT/enhancer binding protein-associated changes of DNA methylation in the angiotensinogen gene. Hypertension, 63(2), 281-288. https://doi.org/10.1161/HYPERTENSIONAHA.113.02303