Transcriptional repression by TGIF2 coordinates neurogenic priming and neural stem cell maintenance

Stem cells balance self-renewal with differentiation. Priming, i.e., low-level expression of differentiation-related genes, enables stem cells to remain undifferentiated and progeny to fast proceed in up-regulation of differentiation genes. Here, we investigated transcriptional priming during neurogenesis to search for key regulators. Assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing of neural stem cells (NSCs) and neurons across forebrain regions identified hundreds of neuronal differentiation genes open while lowly expressed in NSCs. Pantelencephalic candidate transcription factors regulating neurogenic primed genes highlighted the transcriptional repressor transforming growth factor-β-induced homeobox factor 2 (TGIF2). We show that TGIF2 binds and represses neuronal differentiation genes in NSCs by interacting with SIN3 transcription regulator family member A/histone deacetylase corepressor complexes. Gain- and loss-of-function experiments in vitro and in vivo show that TGIF2 maintains NSC identity, slows neuronal differentiation, and regulates more than half of the primed neuronal differentiation genes in NSCs. Together, our database determines primed gene expression across regions and stages and identifies TGIF2 as a key regulator of neurogenic NSC fate.