Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons

Chongyuan Luo, Qian Yi Lee, Orly Wapinski, Rosa Castanon, Joseph R. Nery, Moritz Mall, Michael S. Kareta, Sean M. Cullen, Margaret A. Goodell, Howard Y. Chang, Marius Wernig, Joseph R. Ecker

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8 Scopus citations

Abstract

Direct reprogramming of fibroblasts to neurons induces widespread cellular and transcriptional reconfiguration. Here, we characterized global epigenomic changes during the direct reprogramming of mouse fibroblasts to neurons using whole-genome base-resolution DNA methylation (mC) sequencing. We found that the pioneer transcription factor Ascl1 alone is sufficient for inducing the uniquely neuronal feature of non-CG methylation (mCH), but co-expression of Brn2 and Mytl1 was required to establish a global mCH pattern reminiscent of mature cortical neurons. Ascl1 alone induced promoter CG methylation (mCG) of fibroblast specific genes, while BAM overexpression additionally targets a competing myogenic program and directs a more faithful conversion to neuronal cells. Ascl1 induces local demethylation at its binding sites. Surprisingly, co-expression with Brn2 and Mytl1 inhibited the ability of Ascl1 to induce demethylation, suggesting a contextual regulation of transcription factor - epigenome interaction. Finally, we found that de novo methylation by DNMT3A is required for efficient neuronal reprogramming.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Jan 15 2019

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Keywords

  • DNA methylation
  • epigenetics
  • epigenomics
  • genetics
  • genomics
  • mouse
  • neuron
  • regenerative medicine
  • reprogramming
  • stem cells
  • transdifferentiation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Luo, C., Lee, Q. Y., Wapinski, O., Castanon, R., Nery, J. R., Mall, M., Kareta, M. S., Cullen, S. M., Goodell, M. A., Chang, H. Y., Wernig, M., & Ecker, J. R. (2019). Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons. eLife, 8. https://doi.org/10.7554/eLife.40197