Chromatin accessibility dynamics of neurogenic niche cells reveal defects in neural stem cell adhesion and migration during aging

Robin W Yeo; Olivia Y Zhou; Brian L Zhong; Eric D Sun; Paloma Navarro Negredo; Surag Nair; Mahfuza Sharmin; Tyson J Ruetz; Mikaela Wilson; Anshul Kundaje; Alexander R Dunn; Anne Brunet

doi:10.1038/s43587-023-00449-3

Chromatin accessibility dynamics of neurogenic niche cells reveal defects in neural stem cell adhesion and migration during aging

Nat Aging. 2023 Jul;3(7):866-893. doi: 10.1038/s43587-023-00449-3. Epub 2023 Jul 13.

Authors

Robin W Yeo^#¹, Olivia Y Zhou^#^{1

2

3}, Brian L Zhong⁴, Eric D Sun^{1

5}, Paloma Navarro Negredo¹, Surag Nair⁶, Mahfuza Sharmin^{1

6}, Tyson J Ruetz¹, Mikaela Wilson¹, Anshul Kundaje^{1

6}, Alexander R Dunn⁴, Anne Brunet^{7

8

9}

Affiliations

¹ Department of Genetics, Stanford University, Stanford, CA, USA.
² Stanford Biophysics Program, Stanford University, Stanford, CA, USA.
³ Stanford Medical Scientist Training Program, Stanford University, Stanford, CA, USA.
⁴ Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
⁵ Biomedical Informatics Graduate Program, Stanford University, Stanford, CA, USA.
⁶ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁷ Department of Genetics, Stanford University, Stanford, CA, USA. abrunet1@stanford.edu.
⁸ Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, CA, USA. abrunet1@stanford.edu.
⁹ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. abrunet1@stanford.edu.

^# Contributed equally.

Abstract

The regenerative potential of brain stem cell niches deteriorates during aging. Yet the mechanisms underlying this decline are largely unknown. Here we characterize genome-wide chromatin accessibility of neurogenic niche cells in vivo during aging. Interestingly, chromatin accessibility at adhesion and migration genes decreases with age in quiescent neural stem cells (NSCs) but increases with age in activated (proliferative) NSCs. Quiescent and activated NSCs exhibit opposing adhesion behaviors during aging: quiescent NSCs become less adhesive, whereas activated NSCs become more adhesive. Old activated NSCs also show decreased migration in vitro and diminished mobilization out of the niche for neurogenesis in vivo. Using tension sensors, we find that aging increases force-producing adhesions in activated NSCs. Inhibiting the cytoskeletal-regulating kinase ROCK reduces these adhesions, restores migration in old activated NSCs in vitro, and boosts neurogenesis in vivo. These results have implications for restoring the migratory potential of NSCs and for improving neurogenesis in the aged brain.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Brain
Chromatin* / genetics
Neural Stem Cells*
Neurogenesis / genetics

Substances

Chromatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding