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发育过程中及性别差异对小鼠大脑下丘脑区域的 DNA 甲基化和去甲基化的影响。

Developmental changes and sex differences in DNA methylation and demethylation in hypothalamic regions of the mouse brain.

机构信息

Neuroscience Institute and Center for Behavioral Neuroscience, Georgia State University, Atlanta, GA, USA.

Department of Human Genetics, Emory School of Medicine, Atlanta, GA, USA.

出版信息

Epigenetics. 2020 Jan-Feb;15(1-2):72-84. doi: 10.1080/15592294.2019.1649528. Epub 2019 Aug 3.

Abstract

DNA methylation is dynamically modulated during postnatal brain development, and plays a key role in neuronal lineage commitment. This epigenetic mark has also recently been implicated in the development of neural sex differences, many of which are found in the hypothalamus. The level of DNA methylation depends on a balance between the placement of methyl marks by DNA methyltransferases (Dnmts) and their removal, which is catalyzed by ten-eleven translocation (Tet) methylcytosine dioxygenases. Here, we examined developmental changes and sex differences in the expression of Tet and Dnmt enzymes from birth to adulthood in two hypothalamic regions (the preoptic area and ventromedial nucleus) and the hippocampus of mice. We found highest expression of all Tet enzymes () and Dnmts () in newborns, despite the fact that global methylation and hydroxymethylation were at their lowest levels at birth. Expression of the Dnmt co-activator, , followed a pattern opposite to that of the canonical Dnmts (i.e., was very low in newborns and increased with age). Tet enzyme activity was much higher at birth than at weaning in both the hypothalamus and hippocampus, mirroring developmental changes in gene expression. Sex differences in Tet enzyme expression were seen in all brain regions examined during the first week of life, whereas Dnmt expression was more balanced between the sexes. Neonatal testosterone treatment of females only partially masculinized enzyme expression. Thus, Tet expression and activity are elevated during neonatal brain development, and may play important roles in sexual differentiation of the brain.

摘要

DNA 甲基化在出生后大脑发育过程中动态调节,并在神经元谱系决定中发挥关键作用。这种表观遗传标记最近也与神经性别差异的发展有关,其中许多差异存在于下丘脑。DNA 甲基化的水平取决于 DNA 甲基转移酶 (Dnmts) 放置甲基标记的平衡及其去除,这是由十-十一易位 (Tet) 甲基胞嘧啶双加氧酶催化的。在这里,我们研究了 Tet 和 Dnmt 酶在出生到成年两个下丘脑区域(视前区和腹内侧核)和海马中的表达在性别的发育变化和差异。我们发现所有 Tet 酶()和 Dnmts()在新生儿中的表达最高,尽管在出生时全局甲基化和羟甲基化处于最低水平。Dnmt 共激活剂的表达与经典 Dnmts 的模式相反(即在新生儿中非常低,并随着年龄的增长而增加)。在新生鼠下丘脑和海马中,Tet 酶活性在出生时比断奶时高得多,反映了基因表达的发育变化。在生命的第一周,在所有检查的大脑区域中都观察到 Tet 酶表达的性别差异,而 Dnmt 表达在性别之间更为平衡。新生雌性的睾丸酮处理仅部分使酶表达雄性化。因此,Tet 表达和活性在新生儿大脑发育期间升高,并且可能在大脑的性别分化中发挥重要作用。

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