esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb...

Area of Science:

• Cell Biology
• Epigenetics
• Stem Cell Biology

Background:

• Cytokine Leukemia Inhibitory Factor (LIF) and STAT3 signaling prevent embryonic stem cell (ESC) differentiation.
• In most cell types, STAT3 signaling promotes differentiation, unlike in ESCs.

Purpose of the Study:

• Investigate the role of Brg1, an ATPase subunit of the esBAF chromatin remodeler, in mediating STAT3 binding and LIF signaling in ESCs.
• Elucidate the interplay between Brg1 and Polycomb Repressive Complexes (PcG) in maintaining ESC pluripotency.

Main Methods:

• Chromatin immunoprecipitation (ChIP) to assess STAT3 and PcG binding.
• Analysis of gene expression and chromatin accessibility following Brg1 deletion.
• Genome-wide profiling of Brg1-activated targets and PcG-mediated silencing.

Main Results:

• STAT3 binding in ESCs is dependent on Brg1, which establishes chromatin accessibility at target sites.
• Brg1 deletion results in PcG binding and silencing of LIF pathway genes.
• Brg1 opposes PcG at some loci while reinforcing PcG-mediated repression at classical PcG targets like Hox loci.

Conclusions:

• Brg1 is essential for LIF-STAT3 signaling in ESCs by counteracting PcG repression.
• The esBAF complex, through Brg1, exhibits both antagonistic and synergistic interactions with PcG to maintain pluripotency.
• Brg1 plays a dual role in regulating chromatin, critical for ESC identity.