Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation
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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.
In: Science Advances, Vol. 9, No. 28, eadf9460, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Transcriptional and epigenomic profiling identifies YAP signaling as a key regulator of intestinal epithelium maturation
AU - Pikkupeura, Laura M
AU - Bressan, Raul B
AU - Guiu, Jordi
AU - Chen, Yun
AU - Maimets, Martti
AU - Mayer, Daniela
AU - Schweiger, Pawel J
AU - Hansen, Stine L
AU - Maciag, Grzegorz J
AU - Larsen, Hjalte L
AU - Lõhmussaar, Kadi
AU - Pedersen, Marianne Terndrup
AU - Teves, Joji M Yap
AU - Bornholdt, Jette
AU - Benes, Vladimir
AU - Sandelin, Albin
AU - Jensen, Kim B
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Adult
KW - Humans
KW - Epigenomics
KW - Intestinal Mucosa
KW - Intestines
KW - Epithelium
KW - Chromatin/genetics
U2 - 10.1126/sciadv.adf9460
DO - 10.1126/sciadv.adf9460
M3 - Journal article
C2 - 37436997
VL - 9
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 28
M1 - eadf9460
ER -
ID: 359616021