The interplay of chromatin phase separation and lamina interactions in nuclear organization

Abstract

The genetic material of Eukaryotes is segregated into transcriptionally active euchromatin and silent heterochromatin compartments. The spatial arrangement of chromatin compartments evolves over the course of cellular life in a process that remains poorly understood. The latest nuclear imaging experiments reveal a number of dynamical signatures of chromatin that are reminiscent of active multi-phase liquids. This includes the observations of viscoelastic response, coherent motions, Ostwald ripening, and coalescence of chromatin compartments. There is also growing evidence that liquid-liquid phase separation of protein and nucleic acid components is the underlying mechanism for the liquid behavior of chromatin. In order to dissect the organizational and dynamical implications of chromatin's liquid behavior, we have devised a phenomenological field-theoretic model of the nucleus as a multi-phase condensate of liquid chromatin types. Employing the liquid chromatin model of Drosophila nucleus, we have carried out an extensive set of simulations with an objective to shed light on the dynamics and chromatin patterning observed in the latest nuclear imaging experiments. Specifically, we demonstrate that the emergence of the chromatin mesoscale channels and spheroidal droplets could arise from the interplay of chromatin type to type interactions and the intermingling of chromosomal territories. We also shed light on the dynamical heterogeneity and coherent motions of chromatin domains which are captured by micro-phase separation of chromatin types. Finally, we further illuminate the role of heterochromatin-lamina interactions in the nuclear organization by showing that heterochromatin-lamina interactions enhance the mobility of euchromatin and indirectly introduce correlated motions of heterochromatin droplets.

TAD cliques predict key features of chromatin organization

“…The inverted chromatin organization in rod cell nuclei of nocturnal mammals could provide an interesting model system to explore this further [ 41 ]. Recent chromatin modeling approaches have indeed suggested that heterochromatin-lamina interactions affect the interactivity of domains, and constitute a distinct force shaping nuclear organization [ 42 ]. It is also noteworthy that modeling approaches aiming to reconstitut the conventional (and inverted) center-periphery radial organization of mammalian nuclei critically require a separate force involving lamina-heterochromatin interactions [ 43 ].…”

A simulation model of heterochromatin formation at submolecular detail

“…There is an ongoing effort to computationally and theoretically comprehend molecular structure, function, and properties of the chromatin ( D. Bascom and Schlick, 2018 ; Korolev et al., 2016 ; Laghmach et al., 2021 , 2020 ; Moller and de Pablo, 2020 ; Ozer et al., 2015 ). A number of simulation studies demonstrated that high concentrations of multivalent DNA-binding particles, representing generic transcription factors or epigenetic effectors, drive chromatin condensation, and phase separation ( Barbieri et al., 2012 ; Brackley et al., 2016 ; Jost et al., 2014 ; MacPherson et al., 2018 ; Michieletto et al., 2017a ; Nuebler et al., 2018 ).…”

“…Several other studies focused on the "glassiness" of the condensed chromatin fiber ( Michieletto et al., 2017b ; Shi et al., 2018 ). More generally, ad hoc particle-based simulations proved successful in modeling various aspects of the chromatin structural transformations ( Buckle et al., 2018 ; Falk et al., 2019 ; Gürsoy and Liang, 2016 ; Laghmach et al., 2020 , 2021 ; MacPherson et al., 2018 ; Vasquez et al., 2016 ; Verdaasdonk and Bloom, 2011 ). Worm-like chain is a typical model used to represent the chromatin fiber ( Kang et al., 2015 ; MacPherson et al., 2018 ; Michieletto et al., 2016 , 2017a ; Shi et al., 2018 ).…”

Genome Compartmentalization with Nuclear Landmarks: Random yet Precise

“…They needed to be explicitly accounted for a complete mechanistic understanding of genome organization. [39][40][41][42][43][44] Here, we use a data-driven mechanistic modeling approach to elucidate the mechanisms of global human genome organization. In addition to accounting for the polymeric nature of individual chromosomes, we include particle-based representations for nucleoli, speckles, and nuclear lamina.…”