@article{ee42b5cca4bd4dd299564909bfc403f8,
title = "FOXO3 shares common targets with ASCL1 genome-wide and inhibits ASCL1-dependent neurogenesis",
abstract = "FOXO transcription factors are central regulators of longevity from worms to humans. FOXO3, the FOXO isoform associated with exceptional human longevity, preserves adult neural stem cell pools. Here, we identify FOXO3 direct targets genome-wide in primary cultures of adult neural progenitor cells (NPCs). Interestingly, FOXO3-bound sites are enriched for motifs for bHLH transcription factors, and FOXO3 shares common targets with the proneuronal bHLH transcription factor ASCL1/MASH1 in NPCs. Analysis of the chromatin landscape reveals that FOXO3 and ASCL1 are particularly enriched at the enhancers of genes involved in neurogenic pathways. Intriguingly, FOXO3 inhibits ASCL1-dependent neurogenesis in NPCs and direct neuronal conversion in fibroblasts. FOXO3 also restrains neurogenesis invivo. Our study identifies a genome-wide interaction between the prolongevity transcription factor FOXO3 and the cell-fate determinant ASCL1 and raises the possibility that FOXO3@s ability to restrain ASCL1-dependent neurogenesis may help preserve the neural stem cell pool",
author = "Webb, {Ashley E.} and Pollina, {Elizabeth A.} and Thomas Vierbuchen and Noelia Urb{\'a}n and Duygu Ucar and Leeman, {Dena S.} and Ben Martynoga and Madhavi Sewak and Rando, {Thomas A.} and Fran{\c c}ois Guillemot and Marius Wernig and Anne Brunet",
note = "Funding Information: We thank A. Sidow and of the Sidow lab members A. Valouev, J. Foley, and Z. Weng for ultrahigh-throughput sequencing and for providing bioinformatic tools before publication. We particularly thank A. Valouev for assistance with high-throughput data analyses and B. Benayoun for help with bioinformatics analysis. We thank L. Attardi, J. Baker, A. Gitler, T. Palmer, J. Sage, A. Sidow, A. Valouev, and members of the Brunet lab for critically reading the manuscript. This work was supported by NIH grants R01 AG026648 (A.B.), P01 AG036695 (A.B. and T.A.R.), R01 MH092931 (M.W.), a California Institute for Regenerative Medicine New Faculty Award (A.B.), an Ellison Medical Foundation Senior Award (A.B.), an Ellison Medical Foundation Junior Award (M.W.), and a grant-in-aid U117570528 from the Medical Research Council (F.G.). M.W. is a New York Stem Cell Foundation-Robertson investigator. A.E.W. was supported by a Cancer Biology NIH/NRSA training grant (5T32 CA09302) and by an Ellison Medical Foundation/AFAR postdoctoral fellowship. E.A.P. was supported by an NSF graduate fellowship and an NIH graduate fellowship (F31 AG043232). D.S.L was supported by NDSEG and NSF graduate fellowships. D.S.L. was supported by NDSEG and NSF graduate fellowships. A.E.W. and A.B. conceived and planned the study, and A.E.W. performed experiments. E.A.P. performed the histone mark ChIP-seq studies ( Figure 4 ). E.A.P. and D.S.L. performed the FACS studies in Figures S2 D–S2F, 1 I, and 2 E. E.A.P. and D.S.L. performed the FACS studies in Figures S2 D–S2F, 1 I, and 2 E. D.S.L. also performed the FACS in Figure 7 C. T.V. and M.W. helped with the neurogenesis and iN studies ( Figure 6 ). A.E.W. and A.B. wrote the paper, and all authors provided helpful comments on the manuscript. ",
year = "2013",
doi = "10.1016/j.celrep.2013.06.035",
language = "English",
volume = "4",
pages = "477--491",
journal = "Cell Reports",
issn = "2639-1856",
number = "3",
}