GSE185066
Local euchromatin enrichment in lamina-associated domains anticipates their re-positioning in the adipogenic lineage
Interactions of chromatin with the nuclear lamina via lamina-associated domains (LADs) confers structural stability to the genome. The dynamics of positioning of LADs during differentiation, and how LADs impinge on developmental gene expression, remains elusive, however. We examined changes in the association of lamin B1 with the genome in the first 72 hours of differentiation of adipose stem cells into adipocytes. We demonstrate a repositioning of entire stand-alone LADs and of LAD edges as a prominent nuclear structural feature of early adipogenesis. Whereas adipogenic genes are released from LADs, LADs sequester downregulated or repressed genes irrelevant for the adipose lineage. However, LAD repositioning only partly concurs with gene expression changes. Differentially expressed genes in LADs, including LADs conserved throughout differentiation, reside in local euchromatic and lamin-depleted sub-domains. In these sub-domains, pre-differentiation histone modification profiles correlate with the LAD versus inter-LAD outcome of these genes during adipogenic commitment. In addition, differentially expressed genes in LADs are linked to short-range enhancers which overall co-partition with these genes in LADs versus inter-LADs during differentiation. We conclude that LADs are predictable structural features of adipose nuclear architecture that restrain non-adipogenic genes in a repressive environment. Overall design: We have analyzed nuclear lamin-chromatin contacts throughout in vitro adipose induction of human primary adipose stem cells (ASCs).  We have mapped lamina-associated domains (LADs) by ChIP-seq of lamin B1 on days 0 (here, T00), 1 (T24) and 3 (T72) of differentiation. LADs were also mapped from proliferating (Pro) ASCs in culture, before induction of cell cycle arrest at T00. Gene expression profiles were analyzed by RNA-sequencing at 0, 4, 8, 12, 16, 20, 24 and 72 h after differentiation induction. Histone H3K4me1, H3K4me3 and H3K27ac profiles were determined by ChIP-seq at the same timepoints between 0 and 24 h (T00 to T24). We set out to profile and characterize the fate (outcome) of LADs from T00 to T72, relate LAD changes to geen expression changes in concerved (constitutive) cLADs and in variable vLADs, and relate these changes to histone modification profiles.