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

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.