Restoration of H3k27me3 Modification Epigenetically Silences Cry1 Expression and Sensitizes Leptin Signaling to Reduce Obesity-Related Properties.
Restoration of H3k27me3 Modification Epigenetically Silences Cry1 Expression and Sensitizes Leptin Signaling to Reduce Obesity-Related Properties.
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H3k27me3 修饰的表观遗传修复可沉默 Cry1 表达并增强瘦素信号传导敏感性，从而减少肥胖相关特性
DOI：
10.1002/advs.202004319
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Wei Y;Chen J;Xu X;Li F;Wu K;Jiang Y;Rao Y;Zhao C;Chen W;Wang X
组蛋白H3赖氨酸27（H3 k27 me 3）上的三甲基化可以被组蛋白赖氨酸去甲基化酶6a（Kdm 6a）去除，H3 k27 me 3是允许染色质的转录抑制表观遗传标记。然而，H3 k27 me 3和Kdm 6a对昼夜节律基因的生理功能在很大程度上仍然难以捉摸。通过ChIP-Seq和mRNA微阵列分析，确定了Kdm 6a在调节H3 k27 me 3以影响饮食诱导的肥胖小鼠下丘脑中Crytochrome 1（Cry 1）表达中的关键作用。更重要的是，Kdm 6a的条件性敲除和药理学抑制均降低体重并稳定血糖稳态。虽然Kdm 6a抑制剂不能降低瘦素受体缺陷型db/db小鼠的体重，但它显著降低了Cry 1表达，增强了对外源性瘦素给药的敏感性，并阻断了内源性瘦素缺陷型ob/ob小鼠的体重增加。此外，人类下丘脑的基因分析进一步揭示了Kdm 6a和Cry 1之间的正相关性。结果表明，抑制Kdm 6a可降低Cry 1的表达，并使瘦素信号敏感，从而对抗肥胖相关疾病。因此，它暗示Kdm 6a作为肥胖和代谢紊乱的有吸引力的药物靶标。Kdm 6a的条件性敲除和药理学抑制均降低体重并稳定血糖稳态。抑制Kdm 6a可以恢复H3 k27 me 3修饰，降低下丘脑中Cry 1的表达，并使瘦素信号敏感，以对抗肥胖相关疾病。因此，它暗示Kdm 6a作为肥胖和代谢紊乱的有吸引力的药物靶标。
The trimethylation on histone H3 lysine 27 (H3k27me3), a transcriptionally repressive epigenetic mark of permissive chromatin, can be removed by the histone lysine demethylase 6a (Kdm6a). However, the physiological function of H3k27me3 and Kdm6a on circadian genes remains largely elusive. With the ChIP‐Seq and mRNA microarray assays, a critical role is identified for Kdm6a in the regulation of H3k27me3 to impact the expression of Crytochrome 1 (Cry1) in the hypothalamus of diet induced obesity mice. More importantly, both conditional knockout and pharmacological inhibition of Kdm6a reduce body weight and stabilize blood glucose homeostasis. Although a Kdm6a inhibitor fails to decrease body weight in leptin receptor‐deficient db/db mice, it significantly decreases Cry1 expression, enhances sensitivity to exogenous leptin administration, and blocks body weight increases in endo‐leptin‐deficient ob/ob mice. Moreover, gene analysis of the human hypothalamus further reveals a positive correlation between Kdm6a and Cry1. The results show that inhibition of Kdm6a reduces the Cry1 expression and sensitizes leptin signaling to combat obesity‐related disease. Therefore, it implicates Kdm6a as an attractive drug target for obesity and metabolic disorders. Both conditional knockout and pharmacological inhibition of Kdm6a reduce body weight and stabilize blood glucose homeostasis. Inhibition of Kdm6a restores the H3k27me3 modification, reduces the Cry1 expression in the hypothalamus, and sensitizes leptin signaling to combat obesity‐related disease. Therefore, it implicates Kdm6a as an attractive drug target for obesity and metabolic disorders.
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影响因子：
5.2
作者：
Griebel G;Ravinet-Trillou C;Beeské S;Avenet P;Pichat P
通讯作者：
Pichat P
影响因子：
15.9
作者：
Majumder, Syamantak;Thieme, Karina;Advani, Andrew
通讯作者：
Advani, Andrew
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian
影响因子：
4.8
作者：
Ando, Hitoshi;Kumazaki, Masafumi;Fujimura, Akio
通讯作者：
Fujimura, Akio
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium