Activation of endogenous retroviruses during brain development causes an inflammatory response.
Activation of endogenous retroviruses during brain development causes an inflammatory response.
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内源性逆转录病毒在大脑发育过程中的激活会引起炎症反应。
DOI：
10.15252/embj.2020106423
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发表时间：
2021-05-03
期刊：
影响因子：
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通讯作者：
Jakobsson J
中科院分区：
文献类型：
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作者：
Jönsson ME;Garza R;Sharma Y;Petri R;Södersten E;Johansson JG;Johansson PA;Atacho DA;Pircs K;Madsen S;Yudovich D;Ramakrishnan R;Holmberg J;Larsson J;Jern P;Jakobsson J
内源性逆转录病毒（ERV）占哺乳动物基因组的很大一部分，被认为是导致人类疾病，包括大脑疾病的原因。在大脑中，ERVs的异常激活是炎症反应的潜在触发因素，但对这种现象的机制仍然缺乏深入了解。使用基于CRISPR/Cas9的表观遗传共阻遏蛋白Trim 28的基因破坏，我们发现了增殖神经祖细胞（NPC）中ERVs的动态H3 K9 me 3依赖性调节，但在成年神经元中没有。在小鼠大脑发育过程中，在皮质NPC中体内缺失Trim 28导致在成年大脑的兴奋性神经元中表达高水平ERVs的存活后代。神经元ERV表达与活化的小胶质细胞和聚集样结构中ERV衍生蛋白的存在有关。这项研究表明，大脑发育是沉默ERV的关键时期，并提供了因果关系的体内证据表明，神经元中ERV的转录激活导致炎症反应。表观遗传共阻遏物Trim 28的缺失异常上调内源性逆转录病毒（ERV），导致成年小鼠脑中小胶质细胞活化和ERV衍生蛋白的表达。
Endogenous retroviruses (ERVs) make up a large fraction of mammalian genomes and are thought to contribute to human disease, including brain disorders. In the brain, aberrant activation of ERVs is a potential trigger for an inflammatory response, but mechanistic insight into this phenomenon remains lacking. Using CRISPR/Cas9‐based gene disruption of the epigenetic co‐repressor protein Trim28, we found a dynamic H3K9me3‐dependent regulation of ERVs in proliferating neural progenitor cells (NPCs), but not in adult neurons. In vivo deletion of Trim28 in cortical NPCs during mouse brain development resulted in viable offspring expressing high levels of ERVs in excitatory neurons in the adult brain. Neuronal ERV expression was linked to activated microglia and the presence of ERV‐derived proteins in aggregate‐like structures. This study demonstrates that brain development is a critical period for the silencing of ERVs and provides causal in vivo evidence demonstrating that transcriptional activation of ERV in neurons results in an inflammatory response. Deletion of epigenetic co‐repressor Trim28 aberrantly upregulates endogenous retroviruses (ERV), resulting in microglia activation and the expression of ERV‐derived proteins in adult mouse brains.