SUMMARY 28Cell fate transitions are accompanied by global transcriptional, epigenetic and 29 topological changes driven by transcription factors (TFs), as is strikingly 30 exemplified in somatic cell reprogramming to pluripotent stem cells (PSCs) by 31 OCT4, KLF4, SOX2 and cMYC. How TFs orchestrate the complex molecular 32 changes around their targets in a temporal manner remains largely elusive. Here, 33 using KLF4 as a paradigm, we provide the first TF-centric view of chromatin 34 reorganization during reprogramming and its association to enhancer rewiring 35 and gene regulation. We captured the enhancer connectomes in fibroblasts and 36PSCs by H3K27ac HiChIP and identified complex 3D enhancer hubs that were 37 strongly correlated with cell-type specific gene expression and coregulation. 38 KLF4-centric conformational analysis at different reprogramming stages revealed 39that KLF4 is involved in the dissociation of fibroblast-specific and the 40 establishment of PSC-specific enhancer loops concomitantly with repression or 41 activation of linked genes. Moreover, KLF4 occupancy was significantly enriched 42 within highly connected enhancers, suggesting a role in the formation and 43 regulation of complex enhancer hubs. Indeed, disruption of a single KLF4 binding 44 site from a PSC-specific enhancer was sufficient to reduce expression of multiple 45 genes within the enhancer hub, partly by impairing long-range contact. Our study 46 provides an integrative view of the intricate activities of a master regulator during 47 a controlled cell fate transition and offers novel insights into the order and nature 48 of molecular events that follow TF binding.