神经元早期生命中的基因表达调控持久的表观遗传状态。
Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States.
作者信息
Stroud Hume, Su Susan C, Hrvatin Sinisa, Greben Alexander W, Renthal William, Boxer Lisa D, Nagy M Aurel, Hochbaum Daniel R, Kinde Benyam, Gabel Harrison W, Greenberg Michael E
机构信息
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Cell. 2017 Nov 16;171(5):1151-1164.e16. doi: 10.1016/j.cell.2017.09.047. Epub 2017 Oct 19.
In mammals, the environment plays a critical role in promoting the final steps in neuronal development during the early postnatal period. While epigenetic factors are thought to contribute to this process, the underlying molecular mechanisms remain poorly understood. Here, we show that in the brain during early life, the DNA methyltransferase DNMT3A transiently binds across transcribed regions of lowly expressed genes, and its binding specifies the pattern of DNA methylation at CA sequences (mCA) within these genes. We find that DNMT3A occupancy and mCA deposition within the transcribed regions of genes is negatively regulated by gene transcription and may be modified by early-life experience. Once deposited, mCA is bound by the methyl-DNA-binding protein MECP2 and functions in a rheostat-like manner to fine-tune the cell-type-specific transcription of genes that are critical for brain function.
在哺乳动物中，环境在出生后早期促进神经元发育的最后阶段起着关键作用。虽然表观遗传因素被认为参与了这一过程，但其潜在的分子机制仍知之甚少。在这里，我们表明，在生命早期的大脑中，DNA甲基转移酶DNMT3A短暂地结合在低表达基因的转录区域，其结合决定了这些基因内CA序列（mCA）处的DNA甲基化模式。我们发现，基因转录对基因转录区域内的DNMT3A占据和mCA沉积具有负调控作用，并且可能受到生命早期经历的影响。一旦沉积，mCA就会被甲基化DNA结合蛋白MECP2结合，并以类似变阻器的方式发挥作用，微调对脑功能至关重要的基因的细胞类型特异性转录。
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