Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity.

Autor: Katsuda T; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.; Department of Chemical System Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan., Sussman JH; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.; Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Ito K; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA., Katznelson A; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA., Yuan S; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA., Takenaka N; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA., Li J; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA., Merrell AJ; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA., Cure H; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA., Li Q; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA., Rasool RU; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.; Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA., Asangani IA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.; Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.; Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA., Zaret KS; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. zaret@pennmedicine.upenn.edu.; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA. zaret@pennmedicine.upenn.edu.; Penn Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA. zaret@pennmedicine.upenn.edu., Stanger BZ; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. bstanger@upenn.edu.; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA. bstanger@upenn.edu.; Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA. bstanger@upenn.edu.; The Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA. bstanger@upenn.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Feb 26; Vol. 15 (1), pp. 1761. Date of Electronic Publication: 2024 Feb 26.
DOI: 10.1038/s41467-024-45939-z
Abstrakt: Tissue damage elicits cell fate switching through a process called metaplasia, but how the starting cell fate is silenced and the new cell fate is activated has not been investigated in animals. In cell culture, pioneer transcription factors mediate "reprogramming" by opening new chromatin sites for expression that can attract transcription factors from the starting cell's enhancers. Here we report that SOX4 is sufficient to initiate hepatobiliary metaplasia in the adult mouse liver, closely mimicking metaplasia initiated by toxic damage to the liver. In lineage-traced cells, we assessed the timing of SOX4-mediated opening of enhancer chromatin versus enhancer decommissioning. Initially, SOX4 directly binds to and closes hepatocyte regulatory sequences via an overlapping motif with HNF4A, a hepatocyte master regulatory transcription factor. Subsequently, SOX4 exerts pioneer factor activity to open biliary regulatory sequences. The results delineate a hierarchy by which gene networks become reprogrammed under physiological conditions, providing deeper insight into the basis for cell fate transitions in animals.
(© 2024. The Author(s).)
Databáze: MEDLINE
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