Author: ["Lena Ho","Erik L. Miller","Jehnna L. Ronan","Wen Qi Ho","Raja Jothi","Gerald R. Crabtree"]
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Abstract
The STAT3 transcription factor maintains pluripotency by preventing differentiation. A Brg1-containing chromatin-remodelling complex, esBAF, is shown to direct STAT3 to its targets across the pluripotent genome. Deletion of Brg1 leads to binding of the polycomb complex and subsequent silencing of LIF/STAT targets. Unexpectedly, Brg1 also helps the polycomb complex silence Hox genes thereby further contributing to pluripotency. Signalling by the cytokine LIF and its downstream transcription factor, STAT3, prevents differentiation of pluripotent embryonic stem cells (ESCs). This contrasts with most cell types where STAT3 signalling induces differentiation. We find that STAT3 binding across the pluripotent genome is dependent on Brg1, the ATPase subunit of a specialized chromatin remodelling complex (esBAF) found in ESCs. Brg1 is required to establish chromatin accessibility at STAT3 binding targets, preparing these sites to respond to LIF signalling. Brg1 deletion leads to rapid polycomb (PcG) binding and H3K27me3-mediated silencing of many Brg1-activated targets genome wide, including the target genes of the LIF signalling pathway. Hence, one crucial role of Brg1 in ESCs involves its ability to potentiate LIF signalling by opposing PcG. Contrary to expectations, Brg1 also facilitates PcG function at classical PcG targets, including all four Hox loci, reinforcing their repression in ESCs. Therefore, esBAF does not simply antagonize PcG. Rather, the two chromatin regulators act both antagonistically and synergistically with the common goal of supporting pluripotency.Cite this article
Ho, L., Miller, E., Ronan, J. et al. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nat Cell Biol 13, 903–913 (2011). https://doi.org/10.1038/ncb2285 