Divide and Rule: Phase Separation in Eukaryotic Genome Functioning

Abstract

The functioning of a cell at various organizational levels is determined by the interactions between macromolecules that promote cellular organelle formation and orchestrate metabolic pathways via the control of enzymatic activities. Although highly specific and relatively stable protein-protein, protein-DNA, and protein-RNA interactions are traditionally suggested as the drivers for cellular function realization, recent advances in the discovery of weak multivalent interactions have uncovered the role of so-called macromolecule condensates. These structures, which are highly divergent in size, composition, function, and cellular localization are predominantly formed by liquid-liquid phase separation (LLPS): a physical-chemical process where an initially homogenous solution turns into two distinct phases, one of which contains the major portion of the dissolved macromolecules and the other one containing the solvent. In a living cell, LLPS drives the formation of membrane-less organelles such as the nucleolus, nuclear bodies, and viral replication factories and facilitates the assembly of complex macromolecule aggregates possessing regulatory, structural, and enzymatic functions. Here, we discuss the role of LLPS in the spatial organization of eukaryotic chromatin and regulation of gene expression in normal and pathological conditions.

Anopheles mosquitoes reveal new principles of 3D genome organization in insects

“…If there is no selective pressure maintaining TADs as intact units, why does TADs composition show remarkable similarity within syntenic blocks of species diverged ~100 million years ago? We argue that TADs reflect clustering of chromatin, and principles underlying this clustering, such as Polycomb-mediated interactions 13 , histone interactions 18 , 75 , and organization of other nuclear condensates 76 are conserved across species. Chromatin properties, such as histone modifications are also highly conserved within syntenic blocks 77 .…”

Suppression of liquid–liquid phase separation by 1,6-hexanediol partially compromises the 3D genome organization in living cells

“…This finding is potentially related to the special features of transcriptionally active chromatin, which may form distinct liquid condensates due to the recruitment of multi-bromodomain proteins ( 79 ). Within these condensates, which also contain various components of the transcription machinery and nascent RNAs, associations of remote promoters within transcription factories and enhancer-promoter interactions result in the generation of a network of long-distance contacts ( 85 ). The disruption of liquid condensates associated with active chromatin could, therefore, explain the decrease of long-distance contacts within the A compartment and the establishment of short-distance interactions that could reflect a partial compaction of loci active in Control cells and which is transcriptionally repressed upon 1,6-HD treatment.…”

Dact1 is expressed during chicken and mouse skeletal myogenesis and modulated in human muscle diseases

“…Supramolecular assemblies or membrane-less organelles have been observed in a variety of systems including the nucleolus, speckles, Cajal bodies, and PML bodies (Mitrea et al, 2018a;Razin and Ulianov, 2020). They arise from the ability of proteins with expansive intrinsically disorganized domains (IDRs) to undertake a liquid-liquid phase transition (Garaizar et al, 2020).…”