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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
eLife | 2019

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.

Pubmed ID: 30644360

Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: P20 GM103620
  • Agency: NHGRI NIH HHS, United States
    Id: P50 HG007735
  • Agency: NIDDK NIH HHS, United States
    Id: T32 DK060445
  • Agency: NCI NIH HHS, United States
    Id: R01 CA183252
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK092883
  • Agency: NCI NIH HHS, United States
    Id: P30 CA014195

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