Control of Embryonic Stem Cell Lineage Commitment by Core Promoter Factor, TAF3

Deciphering the molecular basis of pluripotency is fundamental to our understanding of development and embryonic stem cell function. Here, we report that TAF3, a TBP-associated core promoter factor, is highly enriched in ES cells. In this context, TAF3 is required for endoderm lineage differentiation and prevents premature specification of neuroectoderm and mesoderm. In addition to its role in the core promoter recognition complex TFIID, genome-wide binding studies reveal that TAF3 localizes to a subset of chromosomal regions bound by CTCF/cohesin that are selectively associated with genes upregulated by TAF3. Notably, CTCF directly recruits TAF3 to promoter distal sites and TAF3-dependent DNA looping is observed between the promoter distal sites and core promoters occupied by TAF3/CTCF/cohesin. Together, our findings support a new role of TAF3 in mediating long-range chromatin regulatory interactions that safeguard the finely-balanced transcriptional programs underlying pluripotency. [Display omitted] ► High levels of TAF3 in ES cells enable balanced early lineage segregation ► TAF3 is localized to both core promoters and distal enhancer-like sites ► Distal TAF3/CTCF sites distinguish TAF3-activated from TAF3-repressed genes ► Vertebrate-specific domain of TAF3 binds CTCF and mediates DNA looping. At endodermal genes, TAF3 moves beyond its role at the promoter and engages distal enhancers by interacting with CTCF.