Geminin regulates the transcriptional and epigenetic status of neuronal fate-promoting genes during mammalian neurogenesis

Mol Cell Biol. 2012 Nov;32(22):4549-60. doi: 10.1128/MCB.00737-12. Epub 2012 Sep 4.

Abstract

Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein geminin in regulating neurogenesis at a mechanistic level during both Xenopus primary neurogenesis and mammalian neuronal differentiation in vitro. The latter work utilized neural cells derived from embryonic stem and embryonal carcinoma cells in vitro and neural stem cells from mouse forebrain. In all of these contexts, geminin antagonized the ability of neural basic helix-loop-helix (bHLH) transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. However, maintaining geminin at high levels was not sufficient to prevent terminal neuronal differentiation. Therefore, these data support a model whereby geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Differentiation
  • Chromatin / genetics
  • Chromatin / metabolism
  • Embryo, Nonmammalian
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Epigenesis, Genetic*
  • Geminin
  • Gene Expression Regulation, Developmental
  • Histones / genetics
  • Histones / metabolism
  • Mice
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neurogenesis / genetics*
  • Neurons / cytology
  • Neurons / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Prosencephalon / cytology
  • Prosencephalon / embryology
  • Prosencephalon / metabolism*
  • Transcriptional Activation
  • Xenopus Proteins
  • Xenopus laevis / embryology
  • Xenopus laevis / genetics*
  • Xenopus laevis / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • Chromatin
  • GMNN protein, Xenopus
  • Geminin
  • Gmnn protein, mouse
  • Histones
  • Nuclear Proteins
  • Xenopus Proteins