SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis

Proc Natl Acad Sci U S A. 2015 Apr 14;112(15):E1936-45. doi: 10.1073/pnas.1421480112. Epub 2015 Mar 30.

Abstract

Newborn granule neurons generated from neural progenitor cells (NPCs) in the adult hippocampus play a key role in spatial learning and pattern separation. However, the molecular mechanisms that control activation of their neurogenic program remain poorly understood. Here, we report a novel function for the pluripotency factor sex-determining region Y (SRY)-related HMG box 2 (SOX2) in regulating the epigenetic landscape of poised genes activated at the onset of neuronal differentiation. We found that SOX2 binds to bivalently marked promoters of poised proneural genes [neurogenin 2 (Ngn2) and neurogenic differentiation 1 (NeuroD1)] and a subset of neurogenic genes [e.g., SRY-box 21 (Sox21), brain-derived neurotrophic factor (Bdnf), and growth arrest and DNA-damage-inducible, beta (Gadd45b)] where it functions to maintain the bivalent chromatin state by preventing excessive polycomb repressive complex 2 activity. Conditional ablation of SOX2 in adult hippocampal NPCs impaired the activation of proneural and neurogenic genes, resulting in increased neuroblast death and functionally aberrant newborn neurons. We propose that SOX2 sets a permissive epigenetic state in NPCs, thus enabling proper activation of the neuronal differentiation program under neurogenic cue.

Keywords: SOX2; epigenetics; neurogenesis.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Blotting, Western
  • Cell Cycle / genetics
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Epigenesis, Genetic*
  • Gene Expression
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / metabolism*
  • Neurogenesis / genetics*
  • Neurons / metabolism
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • SOXB1 Transcription Factors / deficiency
  • SOXB1 Transcription Factors / genetics*
  • SOXB1 Transcription Factors / metabolism
  • Transcriptional Activation*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Neurod1 protein, mouse
  • Neurog2 protein, mouse
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse