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Profiling of chromatin accessibility in fibroblasts, iPSCs, iPSC-derived neurons and cells overexpressing Onecut transcription factors (OC1, OC2, OC3)

ABSTRACT: 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 here 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 neuronal 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 the potential of ONECUT transcription factors for direct neuronal reprogramming.

ORGANISM(S): Rattus norvegicus Homo sapiens

PROVIDER: GSE120083 | GEO | 2019/04/05

REPOSITORIES: GEO

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Profiling of gene expression using RNA-Seq in fibroblasts, iPSCs, iPSC-derived neurons and cells overexpressing Onecut transcription factors

Project description: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 here 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 neuronal 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 the potential of ONECUT transcription factors for direct neuronal reprogramming.

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A CpG mutational hotspot in a ONECUT (HNF6) binding site accounts for the prevalent variant of Hemophilia B Leyden

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Expression data from E14.5 Onecut1 WT and KO animals

Project description:In this study, we examine the consequences of the loss of two related factors, Onecut1 and Onecut2, during mouse retinal development.

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Expression data from adult Onecut2 WT and KO animals

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Changes in chromatin accessibility and gene expression induced by overexpression of ONECUT transcription factors

Project description:Changes in chromatin accessibility and gene expression induced by overexpression of ONECUT transcription factors

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