Compartment-dependent chromatin interaction dynamics revealed by liquid chromatin Hi-C

Abstract

Highlights• Liquid chromatin Hi-C detects chromatin interaction dissociation rates genome-wide • Chromatin conformations in distinct nuclear compartments differ in stability • Stable heterochromatic associations are major drivers of chromatin phase separation • CTCF-CTCF loops are stabilized by encirclement of loop bases by cohesin ringsFigures 1-7 Methods Supplemental Figures S1-S6 Supplemental Tables S1-S3 Supplemental Movies S1-S2. 2 SUMMARYChromosomes are folded so that active and inactive chromatin domains are spatially segregated. Compartmentalization is thought to occur through polymer phase/microphase separation mediated by interactions between loci of similar type. The nature and dynamics of these interactions are not known. We developed liquid chromatin Hi-C to map the stability of associations between loci. Before fixation and Hi-C, chromosomes are fragmented removing the strong polymeric constraint to enable detection of intrinsic locus-locus interaction stabilities.Compartmentalization is stable when fragments are over 10-25 kb. Fragmenting chromatin into pieces smaller than 6 kb leads to gradual loss of genome organization. Dissolution kinetics of chromatin interactions vary for different chromatin domains. Lamin-associated domains are most stable, while interactions among speckle and polycomb-associated loci are more dynamic.Cohesin-mediated loops dissolve after fragmentation, possibly because cohesin rings slide off nearby DNA ends. Liquid chromatin Hi-C provides a genome-wide view of chromosome interaction dynamics.3

Constricted migration is associated with stable 3D genome structure differences in cancer cell

“…Here, distal is defined as interactions with regions more than 3 Mb away along the chromosome. This measure has previously been associated with changes in chromosome compaction (Heinz et al, 2018) and is related to a measure used to quantify loss of local chromosome structure with chromosome fiber digestion (Belaghzal et al, 2019). We find that in general, where regions along the chromosome strengthen or switch to A compartments, local interactions increase relative to distal (negative DLR value).…”

SPIN reveals genome-wide landscape of nuclear compartmentalization

“…Our SPIN states can be further evaluated and compared using other analysis methods, e.g., polymer simulations (Nuebler et al, 2018), 3D genome structure population modeling (Hua et al, 2018), and integration between chromatin interactome and regulatory network (Tian et al, 2020). In addition, recently published new genome-wide mapping methods (Quinodoz et al, 2018;Beagrie et al, 2017;Zheng et al, 2019) and approaches for assessing chromatin interaction dynamics (Finn et al, 2019;Belaghzal et al, 2019) could be incorporated into our framework. In this work, we made additional attempt to reveal the patterns of consecutive SPIN states on the chromosomes to reveal potential chromatin fiber trajectories with distinct functions (see Supplementary Results, Fig.…”

On the relations of phase separation and Hi-C maps to epigenetics

“…When energy-driven loop extrusion is inhibited by cohesin depletion (analogous to cooling a BCP), HP1 'bridging' of H3K9me2/3-marked nucleosomes within the complexes is reconstituted resulting in de-mixing and micro-phase separation (figure 7f ). Even the smallest heterochromatin-like complexes are likely to phase separate; polymer simulations and chromatin fragmentation experiments indicate that the minimal size of a chromatin 'block' required for phase separation is around 6-20 kb [211,222]. The newly micro-phase-separated complexes (blocks) can then engage in cis-and trans-contacts mediated by HP1 'bridging' of H3K9me2/3-marked nucleosomes (figure 7f and red arrows in the bottom row of figure 7).…”