Marshall Paul R, Zhao Qiongyi, Li Xiang, Wei Wei, Periyakaruppiah Ambika, Zajaczkowski Esmi L, Leighton Laura J, Madugalle Sachithrani U, Basic Dean, Wang Ziqi, Yin Jiayu, Liau Wei-Siang, Gupte Ankita, Walkley Carl R, Bredy Timothy W
Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Cancer and RNA Biology Laboratory, St Vincent's Institute; Department of Medicine, St. Vincent's Hospital, The University of Melbourne; Mary MacKillop Institute for Health Research, Australian Catholic University, Fitzroy, VIC, Australia.
Nat Neurosci. 2020 Jun;23(6):718-729. doi: 10.1038/s41593-020-0627-5. Epub 2020 May 4.
DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Here we show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state-effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.
DNA会形成右手双螺旋之外的构象状态；然而，这些非经典结构在大脑中的功能相关性仍然未知。在这里，我们表明，在小鼠的前额叶皮层中，一种这样的结构——Z-DNA的形成参与了消退记忆的调节。Z-DNA在恐惧学习过程中形成，在消退学习过程中减少，这部分是由Z-DNA与RNA编辑酶Adar1之间的直接相互作用介导的。在恐惧消退学习过程中，Adar1与Z-DNA结合，这导致在Adar1被招募的位点处Z-DNA减少。敲低Adar1会导致无法修改先前获得的恐惧记忆，并阻断DNA结构和RNA状态效应的活动依赖性变化，而全长Adar1的引入可完全挽救这些变化。这些发现提示了一种新的学习诱导基因调节机制，该机制依赖于识别交替DNA结构状态的蛋白质，而这些蛋白质是记忆灵活性所必需的。
