ALKBH1-mediated DNA N6-methyladenine Modification Regulates H3K9me3-dependent Heterochromatin in Neural Tube Development [Cut & Tag]

Neural Tube Defects (NTDs) are a class of severe congenital developmental defects caused by abnormal closure of the neural tube during early embryonic development, including conditions such as anencephaly, spina bifida, and encephalocele. Currently, NTDs are considered to result from the combined effects of genetic and environmental factors, particularly maternal folate intake during pregnancy, leading to widespread epigenetic dysregulation. However, the role of N6-methyladenine (N6-mA) in embryonic neural development remains largely unknown. Here, we found significant upregulation of Alkbh1 and concomitant significant downregulation of overall 6mA in brain tissue of a mouse model of NTDs. Further investigation through MeDIP, CUT&TAG, and single-cell sequencing revealed crosstalk between N6-mA and H3K9me3-marked heterochromatin, primarily impacting the involvement of embryonic glial cells in the formation of the hindbrain during embryonic neural tube development. These findings collectively suggest a potential epigenetic role of N6-mA in mammalian brain development, potentially exhibiting cell type specificity.