Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity

Takeshi Katsuda, Jonathan H. Sussman, Kenji Ito, Andrew Katznelson, Salina Yuan, Naomi Takenaka, Jinyang Li, Allyson J. Merrell, Hector Cure, Qinglan Li, Reyaz Ur Rasool, Irfan A. Asangani, Kenneth S. Zaret () and Ben Z. Stanger ()
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Takeshi Katsuda: University of Pennsylvania
Jonathan H. Sussman: University of Pennsylvania
Kenji Ito: University of Pennsylvania
Andrew Katznelson: University of Pennsylvania
Salina Yuan: University of Pennsylvania
Naomi Takenaka: University of Pennsylvania
Jinyang Li: University of Pennsylvania
Allyson J. Merrell: University of Pennsylvania
Hector Cure: University of Pennsylvania
Qinglan Li: University of Pennsylvania
Reyaz Ur Rasool: University of Pennsylvania
Irfan A. Asangani: University of Pennsylvania
Kenneth S. Zaret: University of Pennsylvania
Ben Z. Stanger: University of Pennsylvania

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-45939-z

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