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

## TL;DR

This study shows that increasing DMTF1 can restore the growth of aged neural stem cells by influencing a specific genetic pathway.

## Contribution

The study identifies DMTF1 as a novel regulator of NSC proliferation via the SWI/SNF-E2F axis in telomere dysfunctional cells.

## Key findings

- DMTF1 up-regulation rescues impaired proliferation of telomere dysfunctional neural stem cells.
- DMTF1 regulates Arid2 and Ss18 genes, which are part of the SWI/SNF complex that promotes NSC proliferation.
- Loss of Arid2 or Ss18 reduces H3K27ac levels and E2F target gene expression, mimicking DMTF1 loss effects.

## Abstract

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.

DMTF1 up-regulation promotes proliferation of “aged” neural stem cells by regulating the SWI/SNF-E2F axis.