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Dynamic chromatin accessibility landscape changes following interleukin-1 stimulation

Matt J. Barter, Kathleen Cheung, Julia Falk, Andreas C. Panagiotopoulos, Caitlin Cosimini, Siobhan O’Brien, Karina Teja-Putri, Graham Neill, David J. Deehan, View ORCID ProfileDavid A. Young
doi: https://doi.org/10.1101/2020.01.29.924878
Matt J. Barter
1Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
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Kathleen Cheung
1Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
2Faculty of Medical Sciences, Bioinformatics Support Unit, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
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Julia Falk
1Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
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Andreas C. Panagiotopoulos
1Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
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Caitlin Cosimini
1Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
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Siobhan O’Brien
1Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
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Karina Teja-Putri
1Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
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Graham Neill
1Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
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David J. Deehan
3Freeman Hospital, Orthopaedics, Freeman Road, High Heaton, Newcastle upon Tyne NE7 7DN
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David A. Young
1Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
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  • ORCID record for David A. Young
  • For correspondence: d.a.young@ncl.ac.uk
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Abstract

Genome-wide methods for examining chromatin modification provide detailed information on regulatory regions of the genome. Dynamic modifications of chromatin allow rapid access of the gene regulatory machinery to condensed genomic regions facilitating subsequent gene expression. Inflammatory cytokine stimulation of cells can cause rapid gene expression changes through direct signalling pathway-mediated transcription factor activation and regulatory element binding.

Here we used the Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) to assess regions of the genome that are differentially accessible following treatment of cells with interleukin-1 (IL-1). We identified 126,483 open chromatin regions, with 241 regions significantly differentially accessible following stimulation, with 64 and 177 more or less accessible, respectively. These differentially accessible regions predominantly correspond to regions of the genome marked as enhancers. Motif searching identified an overrepresentation of a number of transcription factors, most notably RelA in the regions becoming more accessible, with analysis of ChIP-seq data confirmed RelA binding to these regions. A significant correlation in differential chromatin accessibility and gene expression was also observed.

Functionality in regulating gene expression was confirmed using CRISPR/Cas9 genome-editing to delete regions for that became more accessible following stimulation in the genes MMP13, IKBKE and C1QTNF1. These same regions were also accessible for activation using a dCas9-transcriptional activator and showed enhancer activity in a cellular model.

Together, these data describe and functionally validate a number of dynamically accessible chromatin regions involved in inflammatory signalling.

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Posted January 30, 2020.
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Dynamic chromatin accessibility landscape changes following interleukin-1 stimulation
Matt J. Barter, Kathleen Cheung, Julia Falk, Andreas C. Panagiotopoulos, Caitlin Cosimini, Siobhan O’Brien, Karina Teja-Putri, Graham Neill, David J. Deehan, David A. Young
bioRxiv 2020.01.29.924878; doi: https://doi.org/10.1101/2020.01.29.924878
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Dynamic chromatin accessibility landscape changes following interleukin-1 stimulation
Matt J. Barter, Kathleen Cheung, Julia Falk, Andreas C. Panagiotopoulos, Caitlin Cosimini, Siobhan O’Brien, Karina Teja-Putri, Graham Neill, David J. Deehan, David A. Young
bioRxiv 2020.01.29.924878; doi: https://doi.org/10.1101/2020.01.29.924878

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