DMTF1 up-regulation rescues proliferation defect of telomere dysfunctional neural stem cells via the SWI/SNF-E2F axis

Impaired neural stem cell (NSC) proliferation/activation is associated with brain aging, but the underlying mechanisms remain poorly understood. Here, we unexpectedly find that DMTF1, a transcription factor that regulates the Arf/p53 axis in cancer, is down-regulated in the NSCs of a premature aging model driven by telomerase deficiency. DMTF1 up-regulation was able to rescue the impaired proliferation of telomere dysfunctional NSCs. Mechanistically, DMTF1 regulates the transcription of Arid2 and Ss18 genes, two subunits of the SWI/SNF complexes that mediate H3K27ac at E2F gene promoters to promote NSC proliferation. Accordingly, Arid2 or Ss18 depletion phenocopies DMTF1 loss in reducing H3K27ac levels, expression of E2F target genes, and NSC proliferation. Thus, our study has identified DMTF1 as a potential therapeutic target to reverse the proliferation defect of aged NSC that is modeled by telomere attrition and unearthed a distinct genetic program controlled by DMTF1 in NSC.