Global DNA methylation remodeling during direct reprogramming of fibroblasts to neurons
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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.
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Cellular aging features and adult-like neuronal identity of iNs are likely critical for the emergence of such phenotypes in sporadic AD neurons.
“Cellular aging features (Huh et al., 2016; Mertens et al., 2015a, 2018; Tang et al., 2017; Victor et al., 2014) and adult-like neuronal identity of iNs (Luo et al., 2019) are likely critical for the emergence of such phenotypes in sporadic AD neurons, because erasure of aging signatures and re-gaining of fetal identity represents a potent rescue in this study (Miller et al., 2013; Ocampo et al., 2”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Luo et al., 2019
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Acquisition of functional neurons by direct conversion: Switching the developmental clock directly
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Induced Pluripotent Stem Cells; New Tools for Investigating Molecular Mechanisms in Anorexia Nervosa
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Isolation and Neuronal Reprogramming of Mouse Embryonic Fibroblasts
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- Authors
- 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.
- Affiliations
- Salk Institute for Biological Studies (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- Stanford University (US)
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wernig, Marius
- Ecker, Joseph R
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2019-01-15
- Volume
- 8
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6333439
- OpenAlex
- W2952307328
- Cited by
- 76
- References
- 40
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 4 · 2023: 10 · 2022: 11 · 2021: 18 · 2020: 14 · 2019: 6 · 2018: 1
- FWCI
- 4.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases
- Howard Hughes Medical Institute
- National Human Genome Research Institute
- California Institute for Regenerative Medicine
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- direct reprogramming, fibroblast-to-neuron conversion, DNA methylation, non-CG methylation, ASCL1, Brn2, Myt1, Bam, demethylation, DNMT3A, de novo methylation, cortical neurons
- MeSH terms
- DNA Methyltransferase 3A, Animals, DNA (Cytosine-5-)-Methyltransferases, Fibroblasts, Mice, Inbred C57BL, Neurons, Promoter Regions, Genetic, Transcription Factors, Transcription, Genetic, Down-Regulation, Gene Expression Regulation, Developmental, DNA Methylation, Gene Silencing, Cellular Reprogramming
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