The DNA modification N6-methyl-2′-eoxyadenosine (m6dA) drives activity-induced gene expression and is required for fear extinction
The DNA modification N6-methyl-2′-eoxyadenosine (m6dA) drives activity-induced gene expression and is required for fear extinction
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DOI：
10.1038/s41593-019-0339-x
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发表时间：
2019-04-01
影响因子：
25
通讯作者：
Bredy, Timothy W.
中科院分区：
文献类型：
--
作者：
Li, Xiang;Zhao, Qiongyi;Bredy, Timothy W.
众所周知，DNA 修饰可以调节依赖于经验的基因表达。然而，除了胞嘧啶甲基化及其氧化衍生物之外，人们对大脑中其他核碱基化学修饰的功能重要性知之甚少。在这里，我们报告说，在接受恐惧消退训练的成年小鼠中，DNA 修饰 N6-甲基-2'-脱氧腺苷 (m6dA) 沿着启动子和编码序列在激活的前额皮质神经元中积累。 m6dA 的沉积与哺乳动物 m6dA 甲基转移酶 N6amt1 的全基因组占有率增加有关，这与灭绝诱导的基因表达相关。 m6dA 的积累与脑源性神经营养因子 (Bdnf) P4 启动子的转录激活相关，这是 Bdnf 外显子 IV 信使 RNA 表达和条件性恐惧消除所必需的。这些结果扩大了成人大脑中 DNA 修饰的范围，并强调 m6dA 的变化作为与活动诱导的基因表达和恐惧消退记忆形成相关的表观遗传机制。
DNA modification is known to regulate experience-dependent gene expression. However, beyond cytosine methylation and its oxidated derivatives, very little is known about the functional importance of chemical modifications on other nucleobases in the brain. Here we report that in adult mice trained in fear extinction, the DNA modification N6-methyl-2'-deoxyadenosine (m6dA) accumulates along promoters and coding sequences in activated prefrontal cortical neurons. The deposition of m6dA is associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with extinction-induced gene expression. The accumulation of m6dA is associated with transcriptional activation at the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV messenger RNA expression and for the extinction of conditioned fear. These results expand the scope of DNA modifications in the adult brain and highlight changes in m6dA as an epigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.