Cognitive Neuroepigenetics Laboratory, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
Intellectual Development and Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
Nat Neurosci. 2019 Apr;22(4):534-544. doi: 10.1038/s41593-019-0339-x. Epub 2019 Feb 18.
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.
DNA 修饰被认为可以调节经验依赖性基因表达。然而，除了胞嘧啶甲基化及其氧化衍生物之外，对于大脑中其他核碱基的化学修饰在功能上的重要性，我们知之甚少。在这里，我们报告在经过恐惧消退训练的成年小鼠中，DNA 修饰 N6-甲基-2'-脱氧腺苷（m6dA）在前额皮质激活神经元的启动子和编码序列中积累。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，这与消退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，该启动子是 Bdnf 外显子 IV mRNA 表达和条件性恐惧消退所必需的。这些结果扩展了成年大脑中 DNA 修饰的范围，并强调了 m6dA 的变化作为一种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。
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