Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc 
transcription and vascular oxidative stress in obesity

Costantino, Sarah; Paneni, Francesco; Virdis, Agostino; Hussain, Shafaat; Mohammed, Shafeeq Ahmed; Capretti, Giuliana; Akhmedov, Alexander; Dalgaard, Kevin; Chiandotto, Sergio; Pospisilik, John Andrew; Jenuwein, Thomas; Giorgio, Marco; Volpe, Massimo; Taddei, Stefano; Lüscher, Thomas F; Cosentino, Francesco

doi:10.1093/eurheartj/ehx615

アイテム詳細

登録内容を編集ファイル形式で保存

一時保存へ追加

タグ情報を表示リリース履歴を表示詳細要約

公開

学術論文

Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66^Shc transcription and vascular oxidative stress in obesity

MPS-Authors

Dalgaard, Kevin
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons198873

Pospisilik, John Andrew
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons191130

Jenuwein, Thomas
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

External Resource

https://academic.oup.com/eurheartj/article/40/4/383/4565556
(出版社版)

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

フルテキスト (公開)

公開されているフルテキストはありません

付随資料 (公開)

There is no public supplementary material available

引用

Costantino, S., Paneni, F., Virdis, A., Hussain, S., Mohammed, S. A., Capretti, G., Akhmedov, A., Dalgaard, K., Chiandotto, S., Pospisilik, J. A., Jenuwein, T., Giorgio, M., Volpe, M., Taddei, S., Lüscher, T. F., & Cosentino, F. (2017). Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66^Shc transcription and vascular oxidative stress in obesity. European Heart Journal, 40, 383-391. doi:10.1093/eurheartj/ehx615.

引用: https://hdl.handle.net/21.11116/0000-0000-AF58-9

要旨

Aims
Accumulation of reactive oxygen species (ROS) promotes vascular disease in obesity, but the underlying molecular mechanisms remain poorly understood. The adaptor p66^Shc is emerging as a key molecule responsible for ROS generation and vascular damage. This study investigates whether epigenetic regulation of p66^Shc contributes to obesity-related vascular disease.

Methods and results
ROS-driven endothelial dysfunction was observed in visceral fat arteries (VFAs) isolated from obese subjects when compared with normal weight controls. Gene profiling of chromatin-modifying enzymes in VFA revealed a significant dysregulation of methyltransferase SUV39H1 (fold change, −6.9, P < 0.01), demethylase JMJD2C (fold change, 3.2, P < 0.01), and acetyltransferase SRC-1 (fold change, 5.8, P < 0.01) in obese vs. control VFA. These changes were associated with reduced di-(H3K9me2) and trimethylation (H3K9me3) as well as acetylation (H3K9ac) of histone 3 lysine 9 (H3K9) on p66^Shc promoter. Reprogramming SUV39H1, JMJD2C, and SRC-1 in isolated endothelial cells as well as in aortas from obese mice (Lep^Ob/Ob) suppressed p66^Shc-derived ROS, restored nitric oxide levels, and rescued endothelial dysfunction. Consistently, in vivo editing of chromatin remodellers blunted obesity-related vascular p66^Shc expression. We show that SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment to p66^Shc promoter. Indeed, SUV39H1 overexpression in obese mice erased H3K9-related changes on p66^Shc promoter, while SUV39H1 genetic deletion in lean mice recapitulated obesity-induced H3K9 remodelling and p66^Shc transcription.

Conclusion
These results uncover a novel epigenetic mechanism underlying endothelial dysfunction in obesity. Targeting SUV39H1 may attenuate oxidative transcriptional programmes and thus prevent vascular disease in obese individuals.