Alteration of genic 5-hydroxymethylcytosine patterning in olfactory neurons correlates with changes in gene expression and cell identity
Alteration of genic 5-hydroxymethylcytosine patterning in olfactory neurons correlates with changes in gene expression and cell identity
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DOI：
10.1073/pnas.1302759110
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发表时间：
2013-09-03
影响因子：
11.1
通讯作者：
Lomvardas, Stavros
中科院分区：
文献类型：
--
作者：
Colquitt, Bradley M.;Allen, William E.;Lomvardas, Stavros
修饰的DNA碱基5-羟甲基胞嘧啶（5 hmC）在神经元中富集，在那里它可能有助于基因调控和细胞身份。为了确定5 hmC如何影响体内神经元群体中的基因表达，我们评估了主要嗅上皮发育谱系的基底沿着的模式和功能-从多能干细胞到神经元祖细胞到成熟的嗅觉感觉神经元（mOSNs）。我们发现在mOSN发育过程中，5 hmC在基因体上增加，在祖细胞和mOSN阶段之间发生大量模式化。尽管基因体5 hmC水平与所有三种发育细胞类型中的基因表达相关，但这种关联在mOSN中特别明显。Tet 3在mOSNs中的过表达显著改变了基因体5 hmC水平和基因表达，其方式与5 hmC在转录中的积极作用一致。此外，Tet 3过表达破坏嗅觉受体表达和轴突靶向嗅球，嗅觉系统的关键分子和解剖学特征。我们的研究结果表明，基因体5 hmC在转录促进和维持细胞身份独立的功能，作为一个中间体去甲基化的生理重要作用。
The modified DNA base 5-hydroxymethylcytosine (5hmC) is enriched in neurons where it may contribute to gene regulation and cellular identity. To determine how 5hmC influences gene expression in an in vivo neuronal population, we assessed the patterning and function of the base along the developmental lineage of the main olfactory epithelium-from multipotent stem cells through neuronal progenitors to mature olfactory sensory neurons (mOSNs). We find that 5hmC increases over gene bodies during mOSN development with substantial patterning occuring between the progenitor and mOSN stages. Although gene-body 5hmC levels correlate with gene expression in all three developmental cell types, this association is particularly pronounced within mOSNs. Overexpression of Tet3 in mOSNs markedly alters gene-body 5hmC levels and gene expression in a manner consistent with a positive role for 5hmC in transcription. Moreover, Tet3 overexpression disrupts olfactory receptor expression and the targeting of axons to the olfactory bulb, key molecular and anatomical features of the olfactory system. Our results suggest a physiologically significant role for gene-body 5hmC in transcriptional facilitation and the maintenance of cellular identity independent of its function as an intermediate to demethylation.