Constrained release of lamina-associated enhancers and genes from the nuclear envelope during T-cell activation facilitates their association in chromosome compartments

Abstract

The 3D organization of the genome changes concomitantly with expression changes during hematopoiesis and immune activation. Studies 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 sharing 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 reorganization 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 data sets were contrasted with TADs and compartments. Features of specific repositioning events were then tested by fluorescence in situ hybridization during T-cell activation. First, considerable overlap between TADs and LADs was observed with the TAD repositioning as a unit. Second, A1 and A2 subcompartments are segregated in 3D space through differences in proximity to LADs along chromosomes. Third, genes and a putative enhancer in LADs that were released from the periphery during T-cell activation became preferentially associated with A2 subcompartments and were constrained to the relative proximity of the lamina. Thus, lamina associations influence internal nuclear organization, and changes in LADs during T-cell activation may provide an important additional mode of gene regulation.

Revealing Hi-C subcompartments by imputing high-resolution inter-chromosomal chromatin interactions

“…S2C), whereas the facultative heterochromatin mark H3K27me3 becomes more enriched across the A2-B1 boundary. These patterns of changes in epigenomic signals at the boundaries of subcompartments are consistent with changes in histone mark signals at subcompartment boundaries shown by Rao et al (2014) and more recently by Chen et al (2018), and the average log ratio between two epigenomic signals shown by Robson et al (2017). We also observed changes of histone mark signals around A2 and B1 boundaries in downsampled GM12878, K562, and IMR90 using subcompartment annotations from Gaussian HMM clustering ( Fig.…”

Local rewiring of genome–nuclear lamina interactions by transcription

“…We therefore repeated these experiments, but now we employed DamID mapping of lamin B1 interactions. This method has repeatedly been shown to correspond well with FISH microscopy (Guelen et al, 2008;Peric-Hupkes et al, 2010;Harr et al, 2015;Kind et al, 2015;Robson et al, 2017), but it provides much more detailed maps of NL interactions.…”

“…Most genes inside LADs have very low transcriptional activity (Guelen et al, 2008;Peric-Hupkes et al, 2010;Leemans et al, 2019). When cells differentiate, detachment of genes from the NL often coincides with transcriptional activation, while increased NL interactions correlate with reduced transcription (Peric-Hupkes et al, 2010;Lund et al, 2013;Robson et al, 2016Robson et al, , 2017. These observations raise the interesting possibility that the NL helps to establish a repressive environment.…”

A Lamina-Associated Domain Border Governs Nuclear Lamina Interactions, Transcription, and Recombination of the Tcrb Locus

“…The mapping of LADs in human and mouse cell lines by DamID has shown that approximately one-third of the genome is organized into LADs, which typically span 0.1–10 Mb in size (Guelen et al, 2008). LADs and non-LADs are not static subnuclear compartments but can interconvert upon cell differentiation or activation (Peric-Hupkes et al, 2010; Robson et al, 2017). DNA sequence composition (Bian et al, 2013; Meuleman et al, 2013; Zullo et al, 2012), histone modifications (Bian et al, 2013; Towbin et al, 2012), and transcription factors (Harr et al, 2015; Zullo et al, 2012) have all been implicated as molecular regulators of LAD formation.…”