Cellular reprogramming in vivo initiated by SOX4 pioneer factor activity

Area of Science:

• Cell biology
• Developmental biology
• Molecular biology

Background:

• Tissue damage triggers cell fate switching via metaplasia.
• The mechanisms of silencing original cell fates and activating new ones in vivo remain unclear.
• Pioneer transcription factors in cell culture mediate reprogramming by altering chromatin accessibility.

Purpose of the Study:

• To investigate the role of SOX4 in initiating hepatobiliary metaplasia in adult mouse liver.
• To understand the temporal dynamics of SOX4-mediated chromatin changes at regulatory sequences.
• To elucidate the hierarchy of gene network reprogramming during physiological cell fate transitions.

Main Methods:

• Utilizing lineage-traced adult mouse liver models.
• Assessing SOX4's direct binding and regulatory effects on hepatocyte and biliary cell enhancers.
• Analyzing chromatin accessibility changes in response to SOX4 expression.

Main Results:

• SOX4 is sufficient to induce hepatobiliary metaplasia in mice.
• SOX4 initially binds to and represses hepatocyte regulatory sequences by interacting with HNF4A.
• SOX4 subsequently acts as a pioneer factor to open biliary regulatory sequences.

Conclusions:

• SOX4 orchestrates cell fate transitions by sequentially silencing and activating specific gene networks.
• The findings provide a mechanistic understanding of metaplasia initiation in vivo.
• This work deepens insights into the molecular basis of cell fate plasticity in animals.