MiR-138 inhibits EZH2 methyltransferase expression and methylation of histone H3 at lysine 27, and affects thermotolerance acquisition
MiR-138 inhibits EZH2 methyltransferase expression and methylation of histone H3 at lysine 27, and affects thermotolerance acquisition
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DOI：
10.1111/j.1460-9568.2010.07493.x
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发表时间：
2011-01-01
影响因子：
3.4
通讯作者：
Meiri, Noam
中科院分区：
文献类型：
--
作者：
Kisliouk, Tatiana;Yosefi, Sara;Meiri, Noam
热耐受性的获得涉及神经元网络的重塑，因此，在表达的蛋白质库的改变。我们以前已经证明了组蛋白H3甲基化在赖氨酸27（H3 K27）的作用，通过EZH 2甲基转移酶在调控基因表达的关键时期，为建立在鸡的热控制。在这里，我们描述了另一个层次的生物调节，证明了microRNA（miRNA）在调节EZH 2表达的抑制作用，在体温调节系统的发展和功能。在建立热控制的关键时期的热调节期间，在视前下丘脑前部中EZH 2水平增加的同时发生靶向EZH 2的miR-138的表达减少。在关键期颅内注射miR-138导致EZH 2水平短暂降低，同时伴有H3 K27甲基化降低。注射miR-138后进行热调节也消除了热调节期间的EZH 2诱导。此外，这种miR-138诱导的EZH 2在关键期的抑制导致对EZH 2表达的长期影响。处理后一周，在条件和非条件鸡EZH 2蛋白水平是不同的，在他们的盐水注射的同行和变化的方向是彼此相反的。最后，在关键期注射miR-138破坏了体温调节的建立，表现为对热的有缺陷的体温反应。这些数据表明，在调节组蛋白修饰酶的表达的miRNA的作用，从而强调了多层次的调节机制，其中包括在感觉发育的关键时期的神经元网络组织的表观遗传和miRNA的调节机制。
Thermotolerance acquisition involves neuronal network remodeling and, hence, alteration in the repertoire of expressed proteins. We have previously demonstrated the role of histone H3 methylation at lysine 27 (H3K27) by EZH2 methyltransferase in the regulation of gene expression during the critical period for the establishment of thermal control in chicks. Here we describe another level of biological regulation, demonstrating the inhibitory role of microRNAs (miRNAs) in the regulation of EZH2 expression in thermoregulatory system development and functioning. During heat conditioning in the critical period for the establishment of thermal control, a decrease in expression of the EZH2-targeting miR-138 occurred simultaneously with an increase in EZH2 levels in the preoptic anterior hypothalamus. Intracranial injection of miR-138 during the critical period led to a transient reduction in EZH2 levels, which was accompanied by a decrease in H3K27 methylation. Injection of miR-138 followed by heat conditioning also abolished EZH2 induction during heat conditioning. Moreover, this miR-138-induced inhibition of EZH2 during the critical period resulted in a long-term effect on EZH2 expression. A week after the treatment, the EZH2 protein levels in conditioned and in nonconditioned chicks were different from those in their saline-injected counterparts and the directions of change were opposite to each other. Finally, miR-138 injection during the critical period disrupted the establishment of thermoregulation, manifested as a defective body temperature response to heat. These data demonstrate a role for miRNAs in regulating the expression of histone-modifying enzymes, and thus emphasize the multilevel regulation mechanism which includes both epigenetic and miRNA regulatory mechanisms in neuronal network organization during the critical period of sensory development.