JMJD2 regulates enhancer-promoter interactions via biocondensate formation

Enhancer-promoter (E-P) interactions regulate transcription for cell fate determination. However, the regulatory mechanisms of E-P interactions remain elusive. Here, a chromatin interaction-based proteomics approach, LoopID, was developed to profile the proteins at certain E-P anchors, which were termed looposome. Histone demethylase JMJD2, a key looposome component, can regulate E-P interactions and looposome in a catalytic-independent manner through forming biomolecular condensates. Furthermore, a system to engineer E-P interactions was introduced by assembling JMJD2 condensates at certain genomic loci, enabling the construction of cell-type specific E-P interactions to promote cellular reprogramming into pluripotent or 2-cell-like cells. Our findings reveal a non-canonical function of histone demethylase in regulating chromatin organization and provide a strategy for regulating cell fate transitions through E-P interactions.