ONECUT transcription factors induce neuronal characteristics and remodel chromatin accessibility
Publication year
2019Source
Nucleic Acids Research, 47, 11, (2019), pp. 5587-5602ISSN
Publication type
Article / Letter to editor
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Organization
Human Genetics
Cognitive Neuroscience
Molecular Developmental Biology
Journal title
Nucleic Acids Research
Volume
vol. 47
Issue
iss. 11
Page start
p. 5587
Page end
p. 5602
Subject
Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Cognitive Neuroscience - Radboud University Medical Center; Human Genetics - Radboud University Medical Center; Molecular Developmental BiologyAbstract
Remodeling of chromatin accessibility is necessary for successful reprogramming of fibroblasts to neurons. However, it is still not fully known which transcription factors can induce a neuronal chromatin accessibility profile when overexpressed in fibroblasts. To identify such transcription factors, we used ATAC-sequencing to generate differential chromatin accessibility profiles between human fibroblasts and iNeurons, an in vitro neuronal model system obtained by overexpression of Neurog2 in induced pluripotent stem cells (iPSCs). We found that the ONECUT transcription factor sequence motif was strongly associated with differential chromatin accessibility between iNeurons and fibroblasts. All three ONECUT transcription factors associated with this motif (ONECUT1, ONECUT2 and ONECUT3) induced a neuron-like morphology and expression of neuronal genes within two days of overexpression in fibroblasts. We observed widespread remodeling of chromatin accessibility; in particular, we found that chromatin regions that contain the ONECUT motif were in- or lowly accessible in fibroblasts and became accessible after the overexpression of ONECUT1, ONECUT2 or ONECUT3. There was substantial overlap with iNeurons, still, many regions that gained accessibility following ONECUT overexpression were not accessible in iNeurons. Our study highlights both the potential and challenges of ONECUT-based direct neuronal reprogramming.
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