Identification of transcriptional targets of a network of Drosophila core promoter factors in neural stem cells

The transcriptional mechanisms that allow neural stem cells (NSC) to balance self-renewal with differentiation are not well understood. We identify here a unique subset of TATA -binding protein associated factors (TAFs) as NSC identity genes in Drosophila. We found that depletion of any one of nine TAFs or the TBP-related factor 2 (TRF2), resulted in fewer NSCs exhibiting delayed cell cycle progression without impacting NSC survival. In contrast, depletion of TBP led to a delay in NSC cell cycle progression without loss of self-renewal. An integrated RNA-seq and DamID analysis revealed that TAFs function with both TBP and TRF2, and that TAF-TBP and TAF-TRF2 shared targets genes encode different subsets of transcription factors and RNA-binding proteins with established or emerging roles in NSC identity and brain development. Taken together, our results demonstrate that core promoter factors are selectively required for NSC identity in vivo by promoting cell cycle progression, NSC cell polarity and by preventing premature differentiation. Because pathogenic variants in TAF1, TAF2, TAF6, TAF8 and TAF13 have all been linked to human neurological disorders, this work may stimulate and inform future animal models of TAF-linked neurological disorders.