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Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation
During intestinal organogenesis, equipotent epithelial progenitors mature into phenotypically distinct stem cells that are responsible for lifelong maintenance of the tissue. While the morphological changes associated with the transition are well characterized, the molecular mechanisms underpinning...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10337905/ https://www.ncbi.nlm.nih.gov/pubmed/37436997 http://dx.doi.org/10.1126/sciadv.adf9460 |
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author | Pikkupeura, Laura M. Bressan, Raul B. Guiu, Jordi Chen, Yun Maimets, Martti Mayer, Daniela Schweiger, Pawel J. Hansen, Stine L. Maciag, Grzegorz J. Larsen, Hjalte L. Lõhmussaar, Kadi Pedersen, Marianne Terndrup Teves, Joji M. Yap Bornholdt, Jette Benes, Vladimir Sandelin, Albin Jensen, Kim B. |
author_facet | Pikkupeura, Laura M. Bressan, Raul B. Guiu, Jordi Chen, Yun Maimets, Martti Mayer, Daniela Schweiger, Pawel J. Hansen, Stine L. Maciag, Grzegorz J. Larsen, Hjalte L. Lõhmussaar, Kadi Pedersen, Marianne Terndrup Teves, Joji M. Yap Bornholdt, Jette Benes, Vladimir Sandelin, Albin Jensen, Kim B. |
author_sort | Pikkupeura, Laura M. |
collection | PubMed |
description | During intestinal organogenesis, equipotent epithelial progenitors mature into phenotypically distinct stem cells that are responsible for lifelong maintenance of the tissue. While the morphological changes associated with the transition are well characterized, the molecular mechanisms underpinning the maturation process are not fully understood. Here, we leverage intestinal organoid cultures to profile transcriptional, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin conformation landscapes in fetal and adult epithelial cells. We observed prominent differences in gene expression and enhancer activity, which are accompanied by local changes in 3D organization, DNA accessibility, and methylation between the two cellular states. Using integrative analyses, we identified sustained Yes-Associated Protein (YAP) transcriptional activity as a major gatekeeper of the immature fetal state. We found the YAP-associated transcriptional network to be regulated at various levels of chromatin organization and likely to be coordinated by changes in extracellular matrix composition. Together, our work highlights the value of unbiased profiling of regulatory landscapes for the identification of key mechanisms underlying tissue maturation. |
format | Online Article Text |
id | pubmed-10337905 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-103379052023-07-13 Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation Pikkupeura, Laura M. Bressan, Raul B. Guiu, Jordi Chen, Yun Maimets, Martti Mayer, Daniela Schweiger, Pawel J. Hansen, Stine L. Maciag, Grzegorz J. Larsen, Hjalte L. Lõhmussaar, Kadi Pedersen, Marianne Terndrup Teves, Joji M. Yap Bornholdt, Jette Benes, Vladimir Sandelin, Albin Jensen, Kim B. Sci Adv Biomedicine and Life Sciences During intestinal organogenesis, equipotent epithelial progenitors mature into phenotypically distinct stem cells that are responsible for lifelong maintenance of the tissue. While the morphological changes associated with the transition are well characterized, the molecular mechanisms underpinning the maturation process are not fully understood. Here, we leverage intestinal organoid cultures to profile transcriptional, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin conformation landscapes in fetal and adult epithelial cells. We observed prominent differences in gene expression and enhancer activity, which are accompanied by local changes in 3D organization, DNA accessibility, and methylation between the two cellular states. Using integrative analyses, we identified sustained Yes-Associated Protein (YAP) transcriptional activity as a major gatekeeper of the immature fetal state. We found the YAP-associated transcriptional network to be regulated at various levels of chromatin organization and likely to be coordinated by changes in extracellular matrix composition. Together, our work highlights the value of unbiased profiling of regulatory landscapes for the identification of key mechanisms underlying tissue maturation. American Association for the Advancement of Science 2023-07-12 /pmc/articles/PMC10337905/ /pubmed/37436997 http://dx.doi.org/10.1126/sciadv.adf9460 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Pikkupeura, Laura M. Bressan, Raul B. Guiu, Jordi Chen, Yun Maimets, Martti Mayer, Daniela Schweiger, Pawel J. Hansen, Stine L. Maciag, Grzegorz J. Larsen, Hjalte L. Lõhmussaar, Kadi Pedersen, Marianne Terndrup Teves, Joji M. Yap Bornholdt, Jette Benes, Vladimir Sandelin, Albin Jensen, Kim B. Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation |
title | Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation |
title_full | Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation |
title_fullStr | Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation |
title_full_unstemmed | Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation |
title_short | Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation |
title_sort | transcriptional and epigenomic profiling identifies yap signaling as a key regulator of intestinal epithelium maturation |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10337905/ https://www.ncbi.nlm.nih.gov/pubmed/37436997 http://dx.doi.org/10.1126/sciadv.adf9460 |
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