Neurogenin and NeuroD direct transcriptional targets and their regulatory enhancers

EMBO J. 2007 Dec 12;26(24):5093-108. doi: 10.1038/sj.emboj.7601923. Epub 2007 Nov 15.

Abstract

Proneural basic helix-loop-helix proteins are key regulators of neurogenesis but their 'proneural' function is not well understood, partly because primary targets have not been systematically defined. Here, we identified direct transcriptional targets of the bHLH proteins Neurogenin and NeuroD and found that primary roles of these transcription factors are to induce regulators of transcription, signal transduction, and cytoskeletal rearrangement for neuronal differentiation and migration. We determined targets induced in both Xenopus and mouse, which represent evolutionarily conserved core mediators of Neurogenin and NeuroD activities. We defined consensus sequences for Neurogenin and NeuroD binding and identified responsive enhancers in seven shared target genes. These enhancers commonly contained clustered, conserved consensus-binding sites and drove neural-restricted transgene expression in Xenopus embryos. We then used this enhancer signature in a genome-wide computational approach to predict additional Neurogenin/NeuroD target genes involved in neurogenesis. Taken together, these data demonstrate that Neurogenin and NeuroD preferentially recognize neurogenesis-related targets through an enhancer signature of clustered consensus-binding sites and regulate neurogenesis by activating a core set of transcription factors, which build a robust network controlling neurogenesis.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Ectoderm / metabolism
  • Embryo, Nonmammalian / anatomy & histology
  • Embryo, Nonmammalian / physiology
  • Enhancer Elements, Genetic*
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Helix-Loop-Helix Motifs
  • In Situ Hybridization
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • Promoter Regions, Genetic
  • RNA Caps
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Transcription, Genetic*
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism*
  • Xenopus laevis / embryology
  • Xenopus laevis / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • RNA Caps
  • Recombinant Fusion Proteins
  • Xenopus Proteins
  • neurogenin, Xenopus
  • NeuroD protein