KLF4 is involved in the organization and regulation of pluripotency-associated 3D enhancer networks

Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors (TFs), as is exemplified by reprogramming somatic cells to pluripotent stem cells (PSCs) via expression of OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular changes around their target gene loci remains incompletely understood. Here, using KLF4 as a paradigm, we provide a TF-centric view of chromatin reorganization and its association to 3D enhancer rewiring and transcriptional changes during reprogramming of mouse embryonic fibroblasts to PSCs. Inducible depletion of KLF factors in PSCs caused a genome-wide decrease in enhancer connectivity, while disruption of individual KLF4 binding sites within PSC-specific enhancers was sufficient to impair enhancer-promoter contacts and reduce expression of associated genes. Our study provides an integrative view of the complex activities of a lineage-specifying TF and offers novel insights into the nature of molecular events that follow TF binding.