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

The 3D organization of the genome changes concomitantly with expression changes during hematopoeisis and immune activation. However, studies of this phenomenon have focused either on topologically associated domains (TADs) or on lamina-associated domains (LADs) with few studies investigating how TADs and LADs affect one another. To address this we employed a Jurkat T-cell activation system. Lamin B1-DamID was first performed on the resting and activated cells to globally identify all genes moving between the nuclear periphery and the nuclear interior. This identified changes in gene positioning in both directions, though genes being released from the periphery significantly dominated. To assess whether these changes at the nuclear periphery influence wider genome organization, the genes changing in our DamID datasets were contrasted with topologically associated domains (TADs) identified with high resolution in the GM12878 lymphoblastoid cell line. We selected genes that occurred in both LADs and TADs that were released from the periphery during lymphocyte activation. These were tested by fluorescence in situ hybridization finding that the whole TAD moves when an overlapping LAD changes during Jurkat activation and also that higher order TAD compartment interactions are altered. In particular, release of an enhancer from the periphery in the activated cells enabled its association into a higher order TAD-TAD compartment structure. Thus, while TADs are the fundamental unit of genome organization, altered lamina associations clearly influence inter-TAD gene-enhancer interactions as an important additional mode of gene regulation during T-cell activation.