An epigenetic feedback regulatory loop involving microRNA-195 and MBD1 governs neural stem cell differentiation

PLoS One. 2013;8(1):e51436. doi: 10.1371/journal.pone.0051436. Epub 2013 Jan 17.

Abstract

Background: Epigenetic mechanisms, including DNA methylation, histone modification, and microRNAs, play pivotal roles in stem cell biology. Methyl-CpG binding protein 1 (MBD1), an important epigenetic regulator of adult neurogenesis, controls the proliferation and differentiation of adult neural stem/progenitor cells (aNSCs). We recently demonstrated that MBD1 deficiency in aNSCs leads to altered expression of several noncoding microRNAs (miRNAs).

Methodology/principal findings: Here we show that one of these miRNAs, miR-195, and MBD1 form a negative feedback loop. While MBD1 directly represses the expression of miR-195 in aNSCs, high levels of miR-195 in turn repress the expression of MBD1. Both gain-of-function and loss-of-function investigations show that alterations of the MBD1-miR-195 feedback loop tip the balance between aNSC proliferation and differentiation.

Conclusions/significance: Therefore the regulatory loop formed by MBD1 and miR-195 is an important component of the epigenetic network that controls aNSC fate.

Publication types

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

MeSH terms

  • 3' Untranslated Regions / genetics
  • Animals
  • Cell Differentiation / genetics*
  • Cell Proliferation
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • Dentate Gyrus / cytology
  • Epigenesis, Genetic*
  • Feedback, Physiological*
  • Gene Expression Regulation / genetics
  • Gene Knockout Techniques
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / metabolism
  • Phenotype

Substances

  • 3' Untranslated Regions
  • DNA-Binding Proteins
  • MIRN195 microRNA, mouse
  • Mbd1 protein, mouse
  • MicroRNAs