Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis.,Nature Communications

当前位置： X-MOL 学术 › Nat. Commun. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis.
Nature Communications ( IF 14.7 ) Pub Date : 2018-12-07 , DOI: 10.1038/s41467-018-07173-2
Qing-Jun Zhang ₁ , Tram Anh T Tran ₂ , Ming Wang _{1,

3} , Mark J Ranek ₄ , Kristen M Kokkonen-Simon ₄ , Jason Gao ₁ , Xiang Luo ₁ , Wei Tan ₅ , Viktoriia Kyrychenko ₅ , Lan Liao ₆ , Jianming Xu ₆ , Joseph A Hill _{1,

5} , Eric N Olson ₅ , David A Kass ₄ , Elisabeth D Martinez _{2,

7} , Zhi-Ping Liu _{1,

5}

Affiliation

Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.

中文翻译：

组蛋白赖氨酸二甲基去甲基酶 KDM3A 控制病理性心脏肥大和纤维化。

左心室肥厚（LVH）是心血管发病和死亡的主要危险因素。病理性 LVH 涉及转录程序，包括典型胎儿基因和诱导纤维化基因的重新激活。组蛋白赖氨酸去甲基酶（KDM）是癌症转录重编程的新兴调节因子，但它们在异常心脏生长和纤维化中的潜在作用仍知之甚少。在这里，我们研究了 H3K9me2 特异性去甲基酶 Kdm3a 功能的获得和丧失，并表明它会促进压力超负荷时的 LVH 和纤维化。心肌细胞 KDM3A 激活具有促纤维化活性的 Timp1 转录。相比之下，泛 KDM 抑制剂 JIB-04 可以抑制压力过载引起的 LVH 和纤维化。 JIB-04 抑制 KDM3A 并抑制纤维化基因的转录，这些基因与 Kdm3a-KO 小鼠与 WT 对照小鼠中下调的基因重叠。我们的研究为 KDM3A 的促肥大功能提供了遗传和生化证据，并为 KDM 的药理学靶向作为对抗 LVH 和病理性纤维化的有效策略提供了原理证明。

更新日期：2018-12-07

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11