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Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons

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

in Animals / ASCL1 protein / Bioengineering / Brain / Cellular Reprogramming - genetics / Datasets / Demethylation / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA methylation / DNA Methylation - genetics / DNA sequencing / Down-Regulation - genetics / epigenetics / epigenomics / Fibroblasts / Fibroblasts - cytology / Gene expression / Gene Expression Regulation, Developmental / Gene regulation / Gene Silencing / Genetics and Genomics / Genomes / Medicine / Mice, Inbred C57BL / neuron / Neurons / Neurons - cytology / Promoter Regions, Genetic / reprogramming / Stem Cells and Regenerative Medicine / Tools and Resources / Transcription Factors - metabolism / Transcription, Genetic / transdifferentiation

2019

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Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons

2019

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Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons

2019

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Journal Article

Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons

Castanon, Rosa,

Nery, Joseph R,

Kareta, Michael S,

Goodell, Margaret A,

Chang, Howard Y,

Lee, Qian Yi,

Wernig, Marius,

Mall, Moritz,

Wapinski, Orly,

Ecker, Joseph R,

Cullen, Sean M,

Luo, Chongyuan

2019

Overview

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.

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Publisher

eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd

Subject

Animals

/ ASCL1 protein

/ Bioengineering

/ Brain

/ Cellular Reprogramming - genetics

/ Datasets

/ Demethylation