Nuclear Lamin B1 Interactions With Chromatin During the Circadian Cycle Are Uncoupled From Periodic Gene Expression

Abstract

Many mammalian genes exhibit circadian expression patterns concordant with periodic binding of transcription factors, chromatin modifications, and chromosomal interactions. Here we investigate whether chromatin periodically associates with nuclear lamins. Entrainment of the circadian clock is accompanied, in mouse liver, by a net gain of lamin B1–chromatin interactions genome-wide, after which the majority of lamina-associated domains (LADs) are conserved during the circadian cycle. By tailoring a bioinformatics pipeline designed to identify periodic gene expression patterns, we also observe hundreds of variable lamin B1–chromatin interactions among which oscillations occur at 64 LADs, affecting one or both LAD extremities or entire LADs. Only a small subset of these oscillations however exhibit highly significant 12, 18, 24, or 30 h periodicity. These periodic LADs display oscillation asynchrony between their 5′ and 3′ borders, and are uncoupled from periodic gene expression within or in the vicinity of these LADs. Periodic gene expression is also unrelated to variations in gene-to-nearest LAD distances detected during the circadian cycle. Accordingly, periodic genes, including central clock-control genes, are located megabases away from LADs throughout circadian time, suggesting stable residence in a transcriptionally permissive chromatin environment. We conclude that periodic LADs are not a dominant feature of variable lamin B1–chromatin interactions during the circadian cycle in mouse liver. Our results also suggest that periodic hepatic gene expression is not regulated by rhythmic chromatin associations with the nuclear lamina.

Physical constraints in polymer modeling of chromatin associations with the nuclear periphery at kilobase scale

“…Our data argue that the interaction of a chromatin polymer with the nuclear lamina is seeded from the anchors and invokes cooperative recruitment of neighboring beads. In a nucleus context, our models are supported by observations that most of the variability of vLADs invokes extensions of already existing LADs [ 9–11 , 58 , 59 ] or lamina-bound chromatin regions within LADs, rather than binding of domains distant from existing anchors. Our models infer that this cooperative recruitment is enhanced with more rigid heterochromatin domains such as those in bona fide LADs; it is also favored by polymer stretching, altogether demonstrating an interplay between attraction potential, persistence length and distance between anchors.…”

“…In contrast, under similar adsorption-desorption regimes, a more rigid polymer modeling heterochromatin is more prone to undergo long-lasting interactions involving larger domains. Stochasticity in configurations of flexible chromatin polymer models at the lamina therefore concords with the variability of lamin interactions in euchromatic parts of the genome [ 8 , 10 , 11 , 36 , 58 ]. Supporting our polymer models, restrain-based 3D genome models [ 18 , 19 ] also predict more variegated positioning of euchromatic domains at the nuclear periphery across models, recapitulating the cell-to-cell variability in lamin-chromatin contacts.…”

“…(i) Many stochastic interactions can occur along a given polymer segment; this is only possible for flexible polymers ( L P ≪ L C ) and is supported by simulations revealing two (as opposed to one) prevailing configurations (2 trains-1 loop and 3 trains-2 loops). In a chromatin context, our simulation may therefore model lamin interactions with euchromatic sub-LAD domains [ 20 ], punctual sites of phosphorylated lamin A interaction with enhancers [ 15 ], dynamic euchromatic lamin A/C-chromatin interactions [ 11 , 36 ], transient euchromatin interactions with lamin B1 during the circadian cycle [ 58 ], or interactions of lamin B1 with gene-rich euchromatic regions in senescent cells [ 27 ]. (ii) Repeated adsorption/desorption transitions can occur along the chain, giving rise to a polymer ‘breathing’ pattern; this view emerges from one dominant configuration (2 trains-1 loop) in simulations with stretched and semi-flexible to rigid polymers.…”

“…The number of beads in these configurations is homogeneously distributed along the chain, demonstrating variability in the length of these configurations. This could plausibly model rhythmic associations of chromatin with the lamina [ 58 ]. (iii) Lastly, a loop can form at various positions along the chain, yielding 2 trains-1 loop configurations of essentially constant lengths, suggesting a ‘loop sliding’ pattern between the anchors; this is also valid for a stretched or near rigid polymer ( L P L C ).…”

Computational 3D genome modeling using Chrom3D

“…In contrast, facultative fLADs (also called variable vLADs) are by definition more variable between cell types and species; they also harbor a higher gene density and are less heterochromatic than cLADs [41]. Indeed, fLADs are more dynamic during cell differentiation, where entire LADs or LAD sub-domains detach from the nuclear lamina to become non-LAD (or inter-LAD) domains [38,[42][43][44]. Detachment from the nuclear lamina may correlate (though not always) with transcriptional activation of genes within these LADs [45].…”