Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA.
Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC, USA.
Cell Rep. 2021 Apr 6;35(1):108946. doi: 10.1016/j.celrep.2021.108946.
Although embryonic brain development and neurodegeneration have received considerable attention, the events that govern postnatal brain maturation are less understood. Here, we identify the miR-29 family to be strikingly induced during the late stages of brain maturation. Brain maturation is associated with a transient, postnatal period of de novo non-CG (CH) DNA methylation mediated by DNMT3A. We examine whether an important function of miR-29 during brain maturation is to restrict the period of CH methylation via its targeting of Dnmt3a. Deletion of miR-29 in the brain, or knockin mutations preventing miR-29 to specifically target Dnmt3a, result in increased DNMT3A expression, higher CH methylation, and repression of genes associated with neuronal activity and neuropsychiatric disorders. These mouse models also develop neurological deficits and premature lethality. Our results identify an essential role for miR-29 in restricting CH methylation in the brain and illustrate the importance of CH methylation regulation for normal brain maturation.
虽然胚胎大脑发育和神经退行性变受到了相当多的关注，但调控出生后大脑成熟的事件还不太清楚。在这里，我们发现 miR-29 家族在大脑成熟的晚期显著诱导。大脑成熟与 DNMT3A 介导的新生非 CG（CH）DNA 甲基化的短暂、出生后时期有关。我们研究了 miR-29 在大脑成熟过程中的一个重要功能是否是通过靶向 Dnmt3a 来限制 CH 甲基化的时期。在大脑中删除 miR-29 或敲入突变以阻止 miR-29 特异性靶向 Dnmt3a，导致 DNMT3A 表达增加、CH 甲基化增加以及与神经元活动和神经精神疾病相关的基因受到抑制。这些小鼠模型也表现出神经功能缺陷和过早致死。我们的结果确定了 miR-29 在限制大脑中 CH 甲基化中的重要作用，并说明了 CH 甲基化调节对正常大脑成熟的重要性。
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