Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons.

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.

journal_name

Elife

journal_title

eLife

authors

Luo C,Lee QY,Wapinski O,Castanon R,Nery JR,Mall M,Kareta MS,Cullen SM,Goodell MA,Chang HY,Wernig M,Ecker JR

doi

10.7554/eLife.40197

subject

Has Abstract

pub_date

2019-01-15 00:00:00

issn

2050-084X

pii

40197

journal_volume

8

pub_type

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