SRF promotes long-range chromatin loop formation and stem cell pluripotency

Serum response factor (SRF) is a transcription factor essential for cell proliferation, differentiation, and migration, and is required for primitive streak and mesoderm formation in the embryo. The canonical roles of SRF are mediated by a diverse set of context-dependent cofactors. Here we show that SRF physically interacts with CTCF and cohesin subunits at TAD boundaries and loop anchors. SRF reinforces the insulation of TADs and promotes the formation of long-range chromatin loops. In ES cells, SRF associates with Oct4, Sox2, and Nanog and contributes to the formation of 3D pluripotency hubs. Our findings reveal new roles of SRF in higher-order chromatin organization. Overall design: Hi-C analysis in WT and SRF, CTCF, or SRF/CTCF double knock-out non-differentiated or cardiac differentiated mouse ESCs. SRF HiChIP in mouse ESCs. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for SRF in non-differentiated or cardiac differentiated mouse ESCs. Transcriptomes (RNA-Seq) and chromatin accessibility (ATAC-Seq) from non-differentiated or cardiac mesoderm differentiated SRF wild-type and SRF knock-out mouse ESCs.