Genome Compartmentalization with Nuclear Landmarks: Random yet Precise

Abstract

The three-dimensional (3D) organization of eukaryotic genomes plays an important role in genome function. While significant progress has been made in deciphering the folding mechanisms of individual chromosomes, the principles of the dynamic large-scale spatial arrangement of all chromosomes inside the nucleus are poorly understood. We use polymer simulations to model the diploid human genome compartmentalization relative to nuclear bodies such as nuclear lamina, nucleoli, and speckles. We show that a self-organization process based on a co-phase separation between chromosomes and nuclear bodies can capture various features of genome organization, including the formation of chromosome territories, phase separation of A/B compartments, and the liquid property of nuclear bodies. The simulated 3D structures quantitatively reproduce both sequencing-based genomic mapping and imaging assays that probe chromatin interaction with nuclear bodies. Importantly, our model captures the heterogeneous distribution of chromosome positioning across cells, while simultaneously producing well-defined distances between active chromatin and nuclear speckles. Such heterogeneity and preciseness of genome organization can coexist due to the non-specificity of phase separation and the slow chromosome dynamics. Together, our work reveals that the co-phase separation provides a robust mechanism for encoding functionally important 3D contacts without requiring thermodynamic equilibration that can be difficult to achieve.

True-to-scale DNA-density maps correlate with major accessibility differences between active and inactive chromatin

“…Higher order chromatin arrangements differ substantially not only between different cell types and species, but also from cell to cell of a given cell population of the same cell type 5, 13 . This heterogeneity may reflect in part functionally irrelevant stochastic features of 4D spatial genomics, while other features, including the space-time organization of nuclear landscapes at mesoscale, reflect a functionally indispensable preciseness of genome organization 14, 15 (see Discussion).…”

Phase Separation and Correlated Motions in Motorized Genome

“…S1, rather than a lack of parameter fine tuning. Indeed, as recognized in previous studies, explicit interactions with nuclear lamina, 19,32,65,66 separate treatment of intra-and inter-chromosome interactions, 17 or assuming repulsive interactions between the compartments, 18 might be necessary to position B compartments towards the nuclear envelope.…”

“…Euchromatin and heterochromatin are known to exhibit distinct chemical modifications [27][28][29][30] and interact with different regulatory proteins 28,29 and nuclear bodies. 9,[31][32][33] The chemical modifications themselves could drive chromatin demixing by altering nucleosome interactions. For example, acetylation could neutralize the positive charges on histone tails to weaken their binding with DNA, [34][35][36][37] while methylation may lead to under-twisted DNA that strengthens its interactions with histones.…”

Dissecting the co-segregation probability from genome architecture mapping

“…Given that clinical samples are often limited in number and given in a sectioned form, GAM can be more practical than other methods when studying disease-related genome reorganization. While not easily accessible in Hi-C, a number of important properties of 3D genome, such as higher-order chromatin contact (16)(17)(18)(19)(20)(21), lamin and nuclear body association (22)(23)(24)(25)(26), can be measured by leveraging cryoFISH-combined GAM. From an ensemble of cells, Hi-C measures the cross-linking frequencies between two genomic loci; GAM measures the co-segregation frequencies in a nuclear profile; FISH measures the inter-locus spatial distances.…”

“…Given that clinical samples are often limited in number and given in a sectioned form, GAM can be more practical than other methods when studying disease-related genome reorganization. While not easily accessible in Hi-C, a number of important properties of 3D genome, such as higher-order chromatin contact (16–21), lamin and nuclear body association (22–26), can be measured by leveraging cryoFISH-combined GAM.…”