Enhancer-promoter (E-P) interactions regulate transcription during cell fate determination. However, the regulatory mechanisms underlying E-P interactions have remained elusive. Here we present a chromatin-interaction-based proteomic approach, LoopID, to profile proteins (termed the looposome) at certain E-P anchors. We find that histone demethylase JMJD2, a key looposome component, can regulate E-P interactions and the looposome in a catalytic-independent manner through formation of biomolecular condensates. Furthermore, we introduce a system to engineer E-P interactions by assembling JMJD2 condensates at certain genomic loci, enabling construction of cell-type-specific E-P interactions to promote cellular reprogramming into pluripotent or two-cell-like cells. Our findings reveal a noncanonical function of a histone demethylase in regulation of chromatin organization and provide a strategy to regulate cell fate transitions through E-P interactions.
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.