A hierarchy of spatial confinements governs chromatin dynamics and genomic encounters

Abstract

Antibody diversity is generated through stochastic rearrangement of the immunoglobulin heavy chain locus (Igh) involving the recombination of variable (VH), diversity (DH) and joining (JH) gene segments. How coding elements within the Igh locus locate one another in the complex nuclear environment is not understood. Here, we sought to identify the molecular mechanisms and physical principles that govern VH-DHJH genomic encounters. We found that transcription imposed a local confinement that stabilized interactions between spatially proximal genomic elements. The loop anchor CTCF modestly constrained population-average chromatin motion, whereas cohesin-mediated loops established large-scale confinement and reinforced self-similarity of VH-DHJH motion across spatial and temporal scales. Quantitative scaling arguments for first-passage times revealed that encounter frequencies between remote VH-DHJH genomic regions are governed by the interplay of diffusivity and spatial proximity. Together, these findings show that the hierarchy of confinements imposed by transcription and loop extrusion provides the balance between stability and mobility required to regulate genomic encounter frequencies.