Lhx2/Ldb1-mediated trans interactions regulate olfactory receptor choice

The genome is partitioned into topologically associated domains (TADs) and genomic compartments of shared chromatin valance. This architecture is constrained by the DNA polymer, which precludes genic interactions between chromosomes. Here, we report a dramatic divergence from this pattern of nuclear organization that occurs in mouse olfactory sensory neurons (OSNs). In situ HiC on FAC-sorted OSNs and their progenitors shows that olfactory receptor (OR) gene clusters from 18 chromosomes make specific and robust interchromosomal contacts that increase with differentiation. These contacts are orchestrated by intergenic OR enhancers, the Greek Islands, which first contribute to the formation of OR compartments and then form a multi-chromosomal super-enhancer that associates with the single active OR. Greek Island-bound transcription factor Lhx2 and adaptor protein Ldb1 regulate the assembly and maintenance of OR compartments, Greek Island hubs, and OR transcription, providing mechanistic insight and functional support for the role of trans interactions in gene expression.