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Nucleosome dynamics of human iPSC during the early stages of neurodevelopment

Janet C Harwood, View ORCID ProfileNicholas A Kent, Nicholas D Allen, View ORCID ProfileAdrian J Harwood
doi: https://doi.org/10.1101/398792
Janet C Harwood
1MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University, Maindy Rd, Cardiff CF24 4HQ, UK
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Nicholas A Kent
2School of Biosciences, Cardiff University, Museum Ave, Cardiff CF10 3AX, UK
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Nicholas D Allen
2School of Biosciences, Cardiff University, Museum Ave, Cardiff CF10 3AX, UK
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Adrian J Harwood
2School of Biosciences, Cardiff University, Museum Ave, Cardiff CF10 3AX, UK
3Neuroscience and Mental Health Research Institute (NMHRI), Cardiff University, Maindy Rd, Cardiff CF24 4HQ, UK
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  • ORCID record for Adrian J Harwood
  • For correspondence: harwoodaj@cf.ac.uk
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Abstract

Regulation of nucleosome positioning is important for neurodevelopment, and mutation of genes mediating chromatin remodelling are strongly associated with human neurodevelopmental disorders. Unicellular organisms possess arrays of highly positioned nucleosomes within their chromatin, occupying up to 80% of their genomes. These span gene-coding and regulatory regions, and can be associated with local changes of gene transcription. In the much larger genome of human cells, the roles of nucleosome positioning are less clear, and this raises questions of how nucleosome dynamics interfaces with human neurodevelopment.

We have generated genome-wide nucleosome maps from an undifferentiated human induced pluripotent stem cell (hiPSC) line and after its differentiation to the neuronal progenitor cell (NPC) stage. We found that approximately 3% of nucleosomes are highly positioned in NPC. In contrast, there are 8-fold less positioned nucleosomes in pluripotent cells, with the majority arising de novo or relocating during cell differentiation. Positioned nucleosomes do not directly correlate with active chromatin or gene transcription, such as marking Transcriptional Start Sites (TSS). Unexpectedly, we find a small population of nucleosomes that remain positioned after differentiation, occupying similar positions in pluripotent and NPC cells. They flank the binding sites of the key gene regulators NRSF/REST and CTCF, but remain in place whether or not their regulatory complexes are present. Together, these results present an alternative view in human cells, where positioned nucleosomes are sparse and dynamic, but act to alter gene expression at a distance via structural conformation at sites of chromatin regulation, not local changes in gene organisation.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 23, 2018.
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Nucleosome dynamics of human iPSC during the early stages of neurodevelopment
Janet C Harwood, Nicholas A Kent, Nicholas D Allen, Adrian J Harwood
bioRxiv 398792; doi: https://doi.org/10.1101/398792
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Nucleosome dynamics of human iPSC during the early stages of neurodevelopment
Janet C Harwood, Nicholas A Kent, Nicholas D Allen, Adrian J Harwood
bioRxiv 398792; doi: https://doi.org/10.1101/398792

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