Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation.

Autor:	Pikkupeura LM; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Bioinformatics Center, Department of Biology, University of Copenhagen, Copenhagen N DK-2200, Denmark., Bressan RB; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Guiu J; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, 3a planta, Av. Granvia de l'Hospitalet 199, Hospitalet de Llobregat 08908, Spain., Chen Y; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Bioinformatics Center, Department of Biology, University of Copenhagen, Copenhagen N DK-2200, Denmark., Maimets M; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Mayer D; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Schweiger PJ; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Hansen SL; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Maciag GJ; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Larsen HL; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Lõhmussaar K; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Pedersen MT; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark., Teves JMY; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark., Bornholdt J; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Bioinformatics Center, Department of Biology, University of Copenhagen, Copenhagen N DK-2200, Denmark., Benes V; GeneCore, EMBL, Heidelberg, Germany., Sandelin A; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Bioinformatics Center, Department of Biology, University of Copenhagen, Copenhagen N DK-2200, Denmark., Jensen KB; BRIC - Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen N DK-2200, Denmark.; Novo Nordisk Foundation Center for Stem Cell Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N DK-2200, Denmark.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2023 Jul 14; Vol. 9 (28), pp. eadf9460. Date of Electronic Publication: 2023 Jul 12.
DOI:	10.1126/sciadv.adf9460
Abstrakt:	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.
Databáze:	MEDLINE
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