Immune challenge effects on RNA-editing in the human IPSC-derived neurons and microglia-like cells

免疫挑战对人类 IPSC 衍生神经元和小胶质细胞样细胞 RNA 编辑的影响

• 批准号: 2433188
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2433188
• 关键词: Immune; challenge; effects; RNA; editing

Maternal immune activation (MIA) is a known environmental risk factor for neurodevelopmental disorders, established through both epidemiological studies and animal models (Brown & Meyer, 2018). Previous work in the supervisor labs has shown that the effects of cytokine exposure can also be successfully modelled in human induced pluripotent stem cell (iPSC)-derived neurons and these cells exposed to interferon gamma (IFNY) show persistent gene expression changes (Warre-Cornish et al., 2020). However, it remains unknown how the persistency of these changes is mediated.Epigenome and epitranscriptome changes might be among the mechanisms underlying the long-term changes. In the recent years, RNA modifications, including N6-methyladenosine (m6A), have been shown to play important roles in cortical development and exclusively in human m6A tagged transcripts showed enrichment for associations with schizophrenia and autism, suggesting a link between this modification and neurodevelopmental disorders (Yoon et al., 2017). m6A gets deposited on the transcripts by the methyltransferase writer complex (METTL3 and METTL14) and removed by the erasers (FTO and ALKBH5) and functionally this mark is associated with RNA turnover (Roundtree et al., 2017). While loss of the writers complex leads to extended cell cycle and proliferation of neural progenitors (Yoon et al., 2017), to the best of our knowledge, the effects of the eraser loss have not been extensively investigated.Furthermore, recent studies in the immunology field suggest that m6A modifications on viral and cellular RNA play a role in modulating host responses to viral infection (McFadden & Horner, 2021). Some studies have shown that changes in m6A may contribute to the mechanisms microglial inflammatory responses with METTL3 expression is upregulated in response to immune challenge (Wen et al., 2020). In this case, it is feasible that the erasers like ALKBH5 have a modifying function on the response in this case, however, how the eraser loss affects microglia response to immune challenge remains to be investigated. This project aims to explore whether changes in m6A levels increase the susceptibility to neurodevelopmental disease after an immune challenge, using iPSC-derived neurons and microglia like cells as a model for early human brain development.

母体免疫激活（MIA）是神经发育障碍的已知环境风险因素，通过流行病学研究和动物模型建立（Brown & Meyer，2018）。主管实验室的先前工作已经表明，细胞因子暴露的影响也可以在人诱导多能干细胞（iPSC）衍生的神经元中成功建模，并且暴露于干扰素γ（IFNY）的这些细胞显示出持续的基因表达变化（Warre-Cornish et al.，2020年）。表观基因组和表转录组的变化可能是这些变化持续存在的机制之一。近年来，RNA修饰，包括N6-甲基腺苷（m6 A），已显示在皮质发育中起重要作用，并且仅在人类m6 A标记的转录物中显示富集与精神分裂症和自闭症的关联，表明这种修饰与神经发育障碍之间的联系（Yoon et al.，2017年）。m6 A通过甲基转移酶书写复合物（胃L3和胃L14）沉积在转录物上，并通过擦除器（FTO和ALKBH 5）去除，并且在功能上，该标记与RNA周转相关（Roundtree等人，2017年）。虽然书写者复合体的丧失导致细胞周期延长和神经祖细胞增殖（Yoon等人，此外，免疫学领域的最新研究表明，病毒和细胞RNA上的m6 A修饰在调节宿主对病毒感染的反应中发挥作用（McFadden & Horner，2021）。一些研究已经表明，m6 A的变化可能有助于小胶质细胞炎症反应的机制，其中胃L3表达响应于免疫攻击而上调（Wen等人，2020年）。在这种情况下，像ALKBH 5这样的擦除器对这种情况下的反应具有修饰功能是可行的，然而，擦除器丢失如何影响小胶质细胞对免疫攻击的反应仍有待研究。该项目旨在利用iPSC衍生的神经元和小胶质细胞样细胞作为早期人类大脑发育的模型，探索免疫挑战后m6 A水平的变化是否会增加对神经发育疾病的易感性。