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 -