During the humoral immune response, B cells undergo dramatic phenotypic transitions encoded by major transcriptional, epigenetic and genomic architectural changes. How such changes are established remains unknown. Herein, we map and reveal massive reprogramming of regulatory element utilization during the various stages of the humoral immune response. Deconvolution of genome-wide chromatin patterns show that OCT2 is the dominant transcription factor linked to differential accessibility of germinal center (GC) regulatory elements. Strikingly, silent chromatin regions destined to become GC-specific super-enhancers contain pre-positioned OCT2 binding sites in naïve B-cells. These pre-loaded super-enhancer “seeds” featured spatial clustering of DNA regulatory elements enriched in OCT2 DNA binding motifs, that become heavily loaded with OCT2 and its GC specific co-activator OCAB in GC B-cells. Using high resolution chromatin looping assays (Hi-ChIP and 4C), we show that super-enhancers with high abundance of pre-positioned OCT2 binding preferentially form long-range chromatin contacts in GCs, to support expression of GC-specifying factors. Gain in accessibility and architectural interactivity of these regions, as well as maintenance of the GC chromatin and expression patterns were dependent on recruitment of OCAB. Prepositioning key regulators at super-enhancers may represent a broadly used strategy for facilitating rapid cell fate transitions.