Article

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

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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.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NS071153 to B.D. and K01CA190235 and 5-T32HL092332-08 to S.G.), Cancer Prevention Research Institute of Texas (RP150334 and RP160192 to B.D. and C.J.C.), and Sontag Foundation (B.D.).

Author information

Author notes

    • Jeffrey C Carlson
    •  & Wenyi Zhu

    These authors contributed equally to this work.

Affiliations

  1. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.

    • Stacey M Glasgow
    • , Jeffrey C Carlson
    • , Wenyi Zhu
    • , Lesley S Chaboub
    • , Peng Kang
    • , Brittney E Lozzi
    •  & Benjamin Deneen
  2. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.

    • Jeffrey C Carlson
    • , Lesley S Chaboub
    •  & Benjamin Deneen
  3. Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA.

    • Hyun Kyoung Lee
    •  & Benjamin Deneen
  4. Department of Pediatrics, Pediatric Neuroscience Research Program, Papé Family Pediatric Research Institute, Portland, Oregon, USA.

    • Yoanne M Clovis
    •  & Soo-Kyung Lee
  5. Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon, USA.

    • Yoanne M Clovis
    •  & Soo-Kyung Lee
  6. School of Medicine/HHMI, University of California San Diego, San Diego, California, USA.

    • Robert J McEvilly
    •  & Michael G Rosenfeld
  7. Dan L Duncan Cancer Center, Division of Biostatistics, Houston, Texas, USA.

    • Chad J Creighton
  8. Department of Pathology, Texas Children's Hospital, Houston, Texas, USA.

    • Carrie A Mohila
  9. Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.

    • Benjamin Deneen

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Contributions

S.M.G., P.K., and B.D., conceived the project, designed the experiments. S.M.G. and B.D. wrote the manuscript. S.M.G., J.C.C., W.Z., P.K., H.K.L., L.S.C., and B.E.L. performed the experiments. B.D., S.M.G., W.Z., J.C.C., and C.A.M. analyzed the data. R.M., M.G.R., S.-K.L., and Y.M.C. provided essential reagents. C.J.C. provided bioinformatic analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Benjamin Deneen.

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