Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons

Luo, C.; Lee, Q. Y.; Wapinski, O. L.; Castanon, R.; Nery, J. R.; Cullen, S. M.; Goodell, M. A.; Chang, H.; Wernig, M.; Ecker, J. R.

doi:10.1101/371427

bioRxiv · 10.1101/371427

Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons

Luo, C.·Lee, Q. Y.·Wapinski, O. L.·Castanon, R.·Nery, J. R.·Cullen, S. M.·Goodell, M. A.·Chang, H.·Wernig, M.·Ecker, J. R.

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Abstract

Direct reprogramming of fibroblasts to neurons induces widespread cellular and transcriptional reconfiguration. In this study, we characterized global epigenomic changes during direct reprogramming using whole-genome base-resolution DNA methylome (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 strong 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.

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Luo, C., Lee, Q. Y., Wapinski, O. L., Castanon, R., Nery, J. R., Cullen, S. M., Goodell, M. A., Chang, H., Wernig, M., Ecker, J. R.. 2018-07-18. Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons. https://doi.org/10.1101/371427

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