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Impact of sustained transforming growth factor-β receptor inhibition on chromatin accessibility and gene expression in cultured human endometrial MSC
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Lucciola, Raffaella, Vrljicak, Pavle, Gurung, Shanti, Filby, Caitlin, Darzi, Saeedeh, Muter, Joanne, Ott, Sascha, Brosens, Jan J. and Gargett, Caroline E. (2020) Impact of sustained transforming growth factor-β receptor inhibition on chromatin accessibility and gene expression in cultured human endometrial MSC. Frontiers in Cell and Developmental Biology, 8 . 567610. doi:10.3389/fcell.2020.567610 ISSN 2296-634X.
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Official URL: https://doi.org/10.3389/fcell.2020.567610
Abstract
Endometrial mesenchymal stem cells (eMSC) drive the extraordinary regenerative capacity of the human endometrium. Clinical application of eMSC for therapeutic purposes is hampered by spontaneous differentiation and cellular senescence upon large-scale expansion in vitro. A83-01, a selective transforming growth factor-β receptor (TGFβ-R) inhibitor, promotes expansion of eMSC in culture by blocking differentiation and senescence, but the underlying mechanisms are incompletely understood. In this study, we combined RNA-seq and ATAC-seq to study the impact of sustained TGFβ-R inhibition on gene expression and chromatin architecture of eMSC. Treatment of primary eMSC with A83-01 for 5 weeks resulted in differential expression of 1,463 genes. Gene ontology analysis showed enrichment of genes implicated in cell growth whereas extracellular matrix genes and genes involved in cell fate commitment were downregulated. ATAC-seq analysis demonstrated that sustained TGFβ-R inhibition results in opening and closure of 3,555 and 2,412 chromatin loci, respectively. Motif analysis revealed marked enrichment of retinoic acid receptor (RAR) binding sites, which was paralleled by the induction of RARB, encoding retinoic acid receptor beta (RARβ). Selective RARβ inhibition attenuated proliferation and clonogenicity of A83-01 treated eMSC. Taken together, our study provides new insights into the gene networks and genome-wide chromatin changes that underpin maintenance of an undifferentiated phenotype of eMSC in prolonged culture.
| Item Type: | Journal Article | ||||||||||||||||||||||||
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| Subjects: | Q Science > QH Natural history > QH301 Biology | ||||||||||||||||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | ||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Mesenchymal stem cells, Transforming growth factors-beta | ||||||||||||||||||||||||
| Journal or Publication Title: | Frontiers in Cell and Developmental Biology | ||||||||||||||||||||||||
| Publisher: | Frontiers Media | ||||||||||||||||||||||||
| ISSN: | 2296-634X | ||||||||||||||||||||||||
| Official Date: | 1 September 2020 | ||||||||||||||||||||||||
| Dates: |
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| Volume: | 8 | ||||||||||||||||||||||||
| Article Number: | 567610 | ||||||||||||||||||||||||
| DOI: | 10.3389/fcell.2020.567610 | ||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||
| Reuse Statement (publisher, data, author rights): | Copyright © 2020 Lucciola, Vrljicak, Gurung, Filby, Darzi, Muter, Ott, Brosens and Gargett. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | ||||||||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||||||||
| Date of first compliant deposit: | 3 September 2020 | ||||||||||||||||||||||||
| Date of first compliant Open Access: | 7 September 2020 | ||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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