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

Authors :
Pikkupeura LM
Bressan RB
Guiu J
Chen Y
Maimets M
Mayer D
Schweiger PJ
Hansen SL
Maciag GJ
Larsen HL
Lõhmussaar K
Pedersen MT
Teves JMY
Bornholdt J
Benes V
Sandelin A
Jensen KB
Source :
Science advances [Sci Adv] 2023 Jul 14; Vol. 9 (28), pp. eadf9460. Date of Electronic Publication: 2023 Jul 12.
Publication Year :
2023

Abstract

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.

Details

Language :
English
ISSN :
2375-2548
Volume :
9
Issue :
28
Database :
MEDLINE
Journal :
Science advances
Publication Type :
Academic Journal
Accession number :
37436997
Full Text :
https://doi.org/10.1126/sciadv.adf9460