Symmetric neural progenitor divisions require chromatin-mediated homologous recombination DNA repair by Ino80 [ATAC-seq]

Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it also mediates DNA damage repair crucial to proliferating neural progenitor cells (NPCs). Here, we uncover molecularly dissociable roles for nucleosome remodeler INO80 in chromatin-mediated transcriptome and genome maintenance in corticogenesis. We find that conditional Ino80 deletion from cortical NPCs impairs DNA double-strand break repair, triggering p53 activation, robust apoptosis, and microcephaly, whereas co-deletion of Trp53 with Ino80 leads to remarkable reversal of these phenotypes. Using an in vivo DNA repair assay, we find that Ino80 is selectively required for homologous recombination (HR) DNA repair, which is mechanistically distinct from INO80 function in YY1-associated transcription. Unexpectedly, sensitivity to loss of INO80-mediated HR is dependent on the mode of NPC division: Ino80 deletion causes extensive DNA damage and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions. Thus, distinct modes of NPC division have divergent requirements for Ino80-dependent HR DNA repair. We analyzed a total of 2 samples of genomic DNA from E13.5 mouse cortex using ATAC-seq to assess chromatin accessibility. Libraries were generated from 50,000 nuclei per sample following the ATAC-seq protocol from Buenrostro et al. 2015. One control sample and one Emx1-Cre Ino80 conditional mutant sample were used.