Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis

Nat Neurosci. 2017 Nov;20(11):1520-1528. doi: 10.1038/nn.4638. Epub 2017 Sep 11.

Abstract

Long-range enhancer interactions critically regulate gene expression, yet little is known about how their coordinated activities contribute to CNS development or how this may, in turn, relate to disease states. By examining the regulation of the transcription factor NFIA in the developing spinal cord, we identified long-range enhancers that recapitulate NFIA expression across glial and neuronal lineages in vivo. Complementary genetic studies found that Sox9-Brn2 and Isl1-Lhx3 regulate enhancer activity and NFIA expression in glial and neuronal populations. Chromatin conformation analysis revealed that these enhancers and transcription factors form distinct architectures within these lineages in the spinal cord. In glioma models, the glia-specific architecture is present in tumors, and these enhancers are required for NFIA expression and contribute to glioma formation. By delineating three-dimensional mechanisms of gene expression regulation, our studies identify lineage-specific chromatin architectures and associated enhancers that regulate cell fate and tumorigenesis in the CNS.

MeSH terms

  • Animals
  • Base Sequence
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Chick Embryo
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Glioma / genetics*
  • Glioma / metabolism
  • Glioma / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • NFI Transcription Factors / biosynthesis
  • NFI Transcription Factors / genetics*
  • Neuroglia / pathology
  • Neuroglia / physiology*
  • Spinal Cord / growth & development
  • Spinal Cord / metabolism
  • Spinal Cord / pathology

Substances

  • NFI Transcription Factors
  • Nfia protein, mouse