Katznelson, A. | Search bioRxiv

bioRxiv2023

Physiological reprogramming in vivo mediated by Sox4 pioneer factor activity

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 cells enhancers. Here we report that Sox4 is sufficient to initiate hepatobiliary metaplasia in the adult 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 a motif it overlaps with Hnf4a, a hepatocyte master regulator. 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.

cell biology↗

bioRxiv2022

Distinct Chromatin Scanning Modes Lead to Targeting of Compacted Chromatin by Pioneer Factors FOXA1 and SOX2

Pioneer transcription factors, by interacting with nucleosomes, can scan silent, compact chromatin to target gene regulatory sequences, enabling cooperative binding events that modulate local chromatin structure and gene activity. However, pioneer factors do not target all of their cognate motifs and it is unclear whether different pioneers scan compact chromatin the same way. Surprisingly, combined approaches of genomics and single-molecule tracking show that to target DNase-resistant, low-histone turnover sites, pioneer factors can use opposite dynamics of chromatin scanning. FOXA1 uses low nucleoplasmic diffusion and stable chromatin interactions, whereas SOX2 uses high nucleoplasmic diffusion and transient interactions, respectively. Despite such differences, FOXA1 and SOX2 scan low-mobility, silent chromatin to similar extents, as mediated by protein domains outside of the respective DNA binding domains. By contrast, the non-pioneer HNF4A predominantly targets DNase-sensitive, nucleosome-depleted regions. We conclude that the targeting of compact chromatin sites by pioneer factors can be through distinct dynamic processes.

molecular biology↗