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The corepressor NCOR1 and OCT4 facilitate early reprogramming by suppressing fibroblast gene expression
Reprogramming somatic cells to induced pluripotent stem cells (iPSC) succeeds only in a small fraction of cells within the population. Reprogramming occurs in distinctive stages, each facing its own bottlenecks. It initiates with overexpression of transcription factors OCT4, SOX2, KLF4 and c-MYC (OS...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
PeerJ Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183309/ https://www.ncbi.nlm.nih.gov/pubmed/32351783 http://dx.doi.org/10.7717/peerj.8952 |
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author | Peñalosa-Ruiz, Georgina Mulder, Klaas W. Veenstra, Gert Jan C. |
author_facet | Peñalosa-Ruiz, Georgina Mulder, Klaas W. Veenstra, Gert Jan C. |
author_sort | Peñalosa-Ruiz, Georgina |
collection | PubMed |
description | Reprogramming somatic cells to induced pluripotent stem cells (iPSC) succeeds only in a small fraction of cells within the population. Reprogramming occurs in distinctive stages, each facing its own bottlenecks. It initiates with overexpression of transcription factors OCT4, SOX2, KLF4 and c-MYC (OSKM) in somatic cells such as mouse embryonic fibroblasts (MEFs). OSKM bind chromatin, silencing the somatic identity and starting the stepwise reactivation of the pluripotency programme. However, inefficient suppression of the somatic lineage leads to unwanted epigenetic memory from the tissue of origin, even in successfully generated iPSCs. Thus, it is essential to shed more light on chromatin regulators and processes involved in dissolving the somatic identity. Recent work characterised the role of transcriptional corepressors NCOR1 and NCOR2 (also known as NCoR and SMRT), showing that they cooperate with c-MYC to silence pluripotency genes during late reprogramming stages. NCOR1/NCOR2 were also proposed to be involved in silencing fibroblast identity, however it is unclear how this happens. Here, we shed light on the role of NCOR1 in early reprogramming. We show that siRNA-mediated ablation of NCOR1 and OCT4 results in very similar phenotypes, including transcriptomic changes and highly correlated high-content colony phenotypes. Both NCOR1 and OCT4 bind to promoters co-occupied by c-MYC in MEFs. During early reprogramming, downregulation of one group of somatic MEF-expressed genes requires both NCOR1 and OCT4, whereas another group of MEF-expressed genes is downregulated by NCOR1 but not OCT4. Our data suggest that NCOR1, assisted by OCT4 and c-MYC, facilitates transcriptional repression of genes with high expression in MEFs, which is necessary to bypass an early reprogramming block; this way, NCOR1 facilitates early reprogramming progression. |
format | Online Article Text |
id | pubmed-7183309 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | PeerJ Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71833092020-04-29 The corepressor NCOR1 and OCT4 facilitate early reprogramming by suppressing fibroblast gene expression Peñalosa-Ruiz, Georgina Mulder, Klaas W. Veenstra, Gert Jan C. PeerJ Developmental Biology Reprogramming somatic cells to induced pluripotent stem cells (iPSC) succeeds only in a small fraction of cells within the population. Reprogramming occurs in distinctive stages, each facing its own bottlenecks. It initiates with overexpression of transcription factors OCT4, SOX2, KLF4 and c-MYC (OSKM) in somatic cells such as mouse embryonic fibroblasts (MEFs). OSKM bind chromatin, silencing the somatic identity and starting the stepwise reactivation of the pluripotency programme. However, inefficient suppression of the somatic lineage leads to unwanted epigenetic memory from the tissue of origin, even in successfully generated iPSCs. Thus, it is essential to shed more light on chromatin regulators and processes involved in dissolving the somatic identity. Recent work characterised the role of transcriptional corepressors NCOR1 and NCOR2 (also known as NCoR and SMRT), showing that they cooperate with c-MYC to silence pluripotency genes during late reprogramming stages. NCOR1/NCOR2 were also proposed to be involved in silencing fibroblast identity, however it is unclear how this happens. Here, we shed light on the role of NCOR1 in early reprogramming. We show that siRNA-mediated ablation of NCOR1 and OCT4 results in very similar phenotypes, including transcriptomic changes and highly correlated high-content colony phenotypes. Both NCOR1 and OCT4 bind to promoters co-occupied by c-MYC in MEFs. During early reprogramming, downregulation of one group of somatic MEF-expressed genes requires both NCOR1 and OCT4, whereas another group of MEF-expressed genes is downregulated by NCOR1 but not OCT4. Our data suggest that NCOR1, assisted by OCT4 and c-MYC, facilitates transcriptional repression of genes with high expression in MEFs, which is necessary to bypass an early reprogramming block; this way, NCOR1 facilitates early reprogramming progression. PeerJ Inc. 2020-04-22 /pmc/articles/PMC7183309/ /pubmed/32351783 http://dx.doi.org/10.7717/peerj.8952 Text en © 2020 Peñalosa-Ruiz et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited. |
spellingShingle | Developmental Biology Peñalosa-Ruiz, Georgina Mulder, Klaas W. Veenstra, Gert Jan C. The corepressor NCOR1 and OCT4 facilitate early reprogramming by suppressing fibroblast gene expression |
title | The corepressor NCOR1 and OCT4 facilitate early reprogramming by suppressing fibroblast gene expression |
title_full | The corepressor NCOR1 and OCT4 facilitate early reprogramming by suppressing fibroblast gene expression |
title_fullStr | The corepressor NCOR1 and OCT4 facilitate early reprogramming by suppressing fibroblast gene expression |
title_full_unstemmed | The corepressor NCOR1 and OCT4 facilitate early reprogramming by suppressing fibroblast gene expression |
title_short | The corepressor NCOR1 and OCT4 facilitate early reprogramming by suppressing fibroblast gene expression |
title_sort | corepressor ncor1 and oct4 facilitate early reprogramming by suppressing fibroblast gene expression |
topic | Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183309/ https://www.ncbi.nlm.nih.gov/pubmed/32351783 http://dx.doi.org/10.7717/peerj.8952 |
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