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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
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.
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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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