Profiling DNA break sites and transcriptional changes in response to contextual fear learning.
Profiling DNA break sites and transcriptional changes in response to contextual fear learning.
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DOI：
10.1371/journal.pone.0249691
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Tsai LH
中科院分区：
文献类型：
--
作者：
Stott RT;Kritsky O;Tsai LH
神经元活动在体外特定位点产生DNA双链断裂（DSBs），这有助于早期反应基因（ERGs）的快速转录诱导。生理神经元活动，包括小鼠暴露在学习行为中，也会导致dsb的形成，但这些断裂的分布及其与脑功能的关系尚不清楚。在小鼠情境恐惧条件反射（CFC）之后，我们使用γ - h2ax ChIP-Seq分析了DSBs在内侧前额叶皮层和海马中的全基因组位置。值得注意的是，我们发现与培养的原代神经元相比，DSB的形成在大脑中广泛存在，它们主要参与突触过程。我们观察到CFC在神经元和非神经元核中诱导基因的DNA断裂增加。活性调节因子和蛋白酶抑制相关转录因子似乎控制着这些基因在不同细胞类型中的表达变化。最后，我们发现胶质细胞而不是神经元对糖皮质激素有强烈的转录反应，这些基因中的许多都是dsb的位点。我们的研究结果表明，学习行为导致大脑中广泛的DSB形成，这与神经元和神经胶质细胞中经验驱动的转录变化有关。
Neuronal activity generates DNA double-strand breaks (DSBs) at specific loci in vitro and this facilitates the rapid transcriptional induction of early response genes (ERGs). Physiological neuronal activity, including exposure of mice to learning behaviors, also cause the formation of DSBs, yet the distribution of these breaks and their relation to brain function remains unclear. Here, following contextual fear conditioning (CFC) in mice, we profiled the locations of DSBs genome-wide in the medial prefrontal cortex and hippocampus using γH2AX ChIP-Seq. Remarkably, we found that DSB formation is widespread in the brain compared to cultured primary neurons and they are predominately involved in synaptic processes. We observed increased DNA breaks at genes induced by CFC in neuronal and non-neuronal nuclei. Activity-regulated and proteostasis-related transcription factors appear to govern some of these gene expression changes across cell types. Finally, we find that glia but not neurons have a robust transcriptional response to glucocorticoids, and many of these genes are sites of DSBs. Our results indicate that learning behaviors cause widespread DSB formation in the brain that are associated with experience-driven transcriptional changes across both neuronal and glial cells.
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