Lymphocyte genes and an enhancer sequestered at the nuclear periphery undergo constrained release and associate upon T-cell activation

Abstract

AbstractThe 3D organization of the genome changes concomitantly with expression changes during hematopoiesis and immune activation. However, studies of this phenomenon have focused either on lamina-associated domains (LADs) or on topologically-associated domains (TADs), defined by preferential local chromatin interactions, and chromosome compartments, defined as higher-order interactions between TADs in functionally similar states. However, few studies have investigated how these affect one another. To address this, we mapped LADs using Lamin B1-DamID during Jurkat T-cell activation, finding significant genome re-organization at the nuclear periphery dominated by release of loci frequently important for T-cell function. To assess how these changes at the nuclear periphery influence wider genome organization, our DamID datasets were contrasted with TAD contact domains and compartments identified with high resolution in the GM12878 lymphoblastoid cell line. Features of specific repositioning events were then tested by fluorescence in situ hybridization. First, considerable overlap between TAD contact domains and LADs was observed and we found that the TAD repositioned as a unit during T-cell activation. Second, sub-compartments of the A compartment, termed A1 and A2, are segregated in 3D space through differences in proximity to LADs along chromosomes. Third, genes and a putative enhancer that occurred in LADs that were released from the periphery during T-cell activation tended to become associated particularly with A2 sub-compartments and were thus constrained to the relative proximity of the lamina. Thus, lamina-associations clearly influence internal nuclear organization while changes in LADs during T-cell activation may provide an important additional mode of gene regulation.