Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells

J Biol Chem. 2008 Oct 10;283(41):27644-52. doi: 10.1074/jbc.M804899200. Epub 2008 Aug 8.

Abstract

Whether and how mechanisms intrinsic to stem cells modulate their proliferation and differentiation are two central questions in stem cell biology. Although exogenous basic fibroblast growth factor 2 (FGF-2/Fgf-2) is commonly used to expand adult neural stem/progenitor cells (NSPCs) in vitro, we do not yet understand the functional significance or the molecular regulation of Fgf-2 expressed endogenously by adult NSPCs. We previously demonstrated that methylated CpG binding protein 1 (MBD1/Mbd1) is a transcriptional repressor of Fgf-2 and is enriched in adult brains. Mbd1 deficiency in mice selectively affected adult neurogenesis and the differentiation of NSPCs. Here we show that an Mbd1 and DNA methylation-mediated epigenetic mechanism regulated the expression of stem cell mitogen Fgf-2 in adult NSPCs. Mbd1 bound to the Fgf-2 promoter and regulates its expression in adult NSPCs. In the absence of functional Mbd1, the Fgf-2 promoter was hypomethylated, and treatment with a DNA methylation inhibitor resulted in increased Fgf-2 expression in adult NSPCs. We further demonstrated that both acute knockdown of Mbd1 or overexpression of Fgf-2 in adult NSPCs inhibited their neuronal differentiation, which could be responsible for the neurogenic deficits observed in Mbd1-deficient mice. These data indicate that intrinsic epigenetic mechanisms play critical roles in the regulation of adult NSPC functions.

Publication types

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

MeSH terms

  • Adult Stem Cells
  • Animals
  • Cell Differentiation / physiology
  • Cell Proliferation
  • Cells, Cultured
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Epigenesis, Genetic / physiology*
  • Fibroblast Growth Factor 2 / biosynthesis*
  • Fibroblast Growth Factor 2 / genetics
  • Mice
  • Mice, Knockout
  • Mitogens / biosynthesis*
  • Mitogens / genetics
  • Neurons / cytology
  • Neurons / metabolism*
  • Promoter Regions, Genetic / physiology
  • Protein Binding / physiology
  • Rats

Substances

  • DNA-Binding Proteins
  • Mbd1 protein, mouse
  • Mbd1 protein, rat
  • Mitogens
  • Fibroblast Growth Factor 2