TEAD2 initiates ground-state pluripotency by mediating chromatin looping.

The transition of mouse embryonic stem cells (ESCs) between serum/LIF and 2i(MEK and GSK3 kinase inhibitor)/LIF culture conditions serves as a valuable model for exploring the mechanisms underlying ground and confused pluripotent states. Regulatory networks comprising core and ancillary pluripotency factors drive the gene expression programs defining stable naïve pluripotency. In our study, we systematically screened factors essential for ESC pluripotency, identifying TEAD2 as an ancillary factor maintaining ground-state pluripotency in 2i/LIF ESCs and facilitating the transition from serum/LIF to 2i/LIF ESCs. TEAD2 exhibits increased binding to chromatin in 2i/LIF ESCs, targeting active chromatin regions to regulate the expression of 2i-specific genes. In addition, TEAD2 facilitates the expression of 2i-specific genes by mediating enhancer-promoter interactions during the serum/LIF to 2i/LIF transition. Notably, deletion of Tead2 results in reduction of a specific set of enhancer-promoter interactions without significantly affecting binding of chromatin architecture proteins, CCCTC-binding factor (CTCF), and Yin Yang 1 (YY1). In summary, our findings highlight a novel prominent role of TEAD2 in orchestrating higher-order chromatin structures of 2i-specific genes to sustain ground-state pluripotency. Synopsis: The transition of mouse embryonic stem cells (ESCs) between ground and confused state culture conditions unveils transcriptional networks governing pluripotency. In this study, we identified TEAD2 as a key ESC regulator initiating pluripotency through mediating 2i (MEK and GSK3 kinase inhibitor) state-specific chromatin looping and genome architecture. TEAD2 supports the ground-state of pluripotency and facilitates the conversion from serum/LIF to 2i/LIF ESCs. Genome-wide TEAD2 occupancy is increased in 2i/LIF ESCs, targeting active chromatin regions at 2i-specific genes. TEAD2 promotes 2i-specific gene expression by mediating enhancer-promoter interactions. Mutation of TEAD2 binding sites at B4galt6 promoter disrupts enhancer-promoter interactions at this 2i-specific gene locus. The transcription factor TEAD2 aids naïve pluripotency of mouse embryonic stem cells by orchestrating state-specific genome architecture. [ABSTRACT FROM AUTHOR]