Phase-separation in chromatin organization
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Ó Indian Academy of Sciences ( 01234567 89().,-volV)( 01234567 89().,-volV)
Perspectives Phase-separation in chromatin organization GEETA J NARLIKAR Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA (Email, [email protected])
The organization of chromatin into different types of compact versus open states provides a means to fine tune gene regulation. Recent studies have suggested a role for phase-separation in chromatin compaction, raising new possibilities for regulating chromatin compartments. This perspective discusses some specific molecular mechanisms that could leverage such phase-separation processes to control the functions and organization of chromatin. Keywords.
Histone; nucleosome; heterochromatin; phase-separation; auto-inhibition
The nucleus is a crowded mixture of macromolecules with chromatin comprising a dominant component (Hancock and Jeon 2014). Despite such crowding, distinct sophisticated activities occur within the nucleus with high specificity. Phase-separation, a long-observed property of macromolecules at high concentration, provides one vantage point to explain how intra-nuclear organization might occur in a crowded milieu. In its simplest form, phaseseparation refers to the process where a mixture of components in solution de-mix (separate) into two or more distinct phases with different physical and chemical properties (Hyman et al. 2014; Alberti et al. 2019). At one extreme, this process describes the non-functional aggregation of misfolded proteins. At another extreme, this process describes the formation of functional liquid-like compartments formed by the macromolecules that de-mix from solution. This latter form of phase-separation has been termed liquid–liquid phase-separation (LLPS). In LLPS driven states, nucleation and condensation of the component macromolecules are proposed to drive the formation of liquid droplets with differentiated material and chemical micro-environments (Hyman et al. 2014; Alberti et al. 2019). Over the last several decades, chemists, physicists and material scientists have studied the conditions that This artice is part of the Topical Collection: Chromatin Biology and Epigenetics. http://www.ias.ac.in/jbiosci
promote LLPS in model systems (Hancock and Jeon 2014). These studies have identified several key determinants that promote LLPS: (i) the polymeric nature of the component macromolecules; (ii) the ability of molecules to form multi-valent interactions; (iii) intrinsically disordered regions (IDRs) within proteins that can participate in multivalent interactions; and (iv) macromolecular crowding. The eukaryotic nucleus has an abundance of these determinants. For example, (i) chromatinized DNA provides long polymers, (ii) intrinsically disordered histone tails participate in multi-valent interactions between nucleosomes, and (iii) macromolecular concentrations within a eukaryotic nucleus can reach up to 400 mg/ml (Hancock and Jeon 2014) (figure 1). Consistent with these determinants, a series of stu
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