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. 2022 Jul 5:15:25168657221109766.
doi: 10.1177/25168657221109766. eCollection 2022.

HP1-Driven Micro-Phase Separation of Heterochromatin-Like Domains/Complexes

Prim B Singh  1 , Andrew G Newman  2
Affiliations

HP1-Driven Micro-Phase Separation of Heterochromatin-Like Domains/Complexes

Prim B Singh et al. Epigenet Insights. .
No abstract available

Keywords: H3K9me3; HP1; Heterochromatin; Hi-C; phase separation.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Figures

Figure 1.
Figure 1.
Liquid-liquid phase separation (LLPS) vs collapsed globule: (a) A model for HP1-driven LLPS that forms a liquid droplet surrounding constitutive heterochromatin. HP1 dimers ‘bridge’ within and between ‘clutches’ of H3K9me3-marked nucleosomes (orange circles). When the concentration of HP1 dimers reaches a critical concentration HP1-driven LLPS (purple sphere with HP1 proteins in the nucleoplasm) drives soluble heterochromatic nucleosomes into droplets that separate constitutive heterochromatin from the surrounding euchromatin (grey circles), forming a boundary that is selectively permeable to molecules based on their chemical properties., Depicted are molecules (blue circles) that can cross the droplet boundary and others that cannot (green circles). (b) The collapsed globule model for constitutive heterochromatin envisages the collapsed state as being caused by homotypic DNA repetitive elements, nucleosome-nucleosome interactions and chromatin ‘bridging’ proteins. HP1 might stabilise the heterochromatic collapsed globule state through bridging between and within between ‘clutches’ of H3K9me3-marked nucleosomes (orange circles) but is not alone sufficient to establish the collapsed state.
Figure 2.
Figure 2.
Microphase separation of heterochromatin-like domains/complexes at the KRAB-ZNF clusters on human chromosome 19 and their relation to the heterochromatic B4 sub-compartment: (a) A small (~1.5 kb) ATRX-containing heterochromatin-like complex nucleates the large domains at the KRAB-ZNF clusters on human chromosome 19 (taken and modified from). (1) The KRAB-ZNF binds to its DNA binding site through its zinc-fingers (Zn). (2) The KRAB domain of the KRAB-ZNF interacts with KAP1. An HP1 CSD dimer binds to one molecule of KAP1. The HP1 CD binds to H3K9me3. (3) The SUMOylated bromodomain of KAP1 interacts with SETDB1 H3K9 HMTase. (4) SETDB1 generates H3K9me3 (red circles). (5) The ATRX/DAXX complex is bound to KAP1, HP1 and H3K9me3. ATRX/DAXX incorporates replacement histone H3.3 into chromatin thereby reinforcing nucleation. (6) HP1 recruits a H4K20 HMTase that generates H4K20me3 (green circles). (7) KAP1 binds to the maintenance DNA methylase DNMT1 and its co-factor Np95. DNMT1 maintains cytosine methylation at the site of assembly. (b) Model depicting SUV39H1-mediated spreading of H3K9me3 and HP1 proteins that form the larger KRAB-ZNF domain (taken and modified from). In top left panel, the nucleation complex (shown in (a) generates H3K9me3-marked nucleosomes (red filled circles) in ‘clutches’ on either side of the complex. In top right panel, the CD of SUV39H1 attaches to H3K9me3-marked nucleosomes within a clutch whereupon the SUV39H1 SET domain catalyses methylation of H3K9, providing a positive feedback loop that enables spreading of the domain in the 5′ direction away from the nucleation site. In bottom left panel, SUV39H1 regulates spreading of H3K9me3 along the chromatin fibre (red arrow). The size of the ‘clutches’ formed in the wake of the newly-deposited H3K9me3 is determined by the sum of competing free-energy contributions of interaction energy and elastic energy that result from binding of HP1 dimers to H3K9me3-marked nucleosomes. In bottom right panel, H3K9me3 continues to spread by SUV39H1 activity (red arrow) and HP1-mediated bridging of H3K9me3-marked nucleosomes within and between ‘clutches’. (c) The heterochromatic B4 sub-compartment overlaps exactly with chromosomal regions enriched for HP1β, KAP1 and H3K9me3 (only the q arm is shown; taken and modified from Ref.). The interactions of 2 KRAB-ZNF domains that contribute contact enrichments to the B4 sub-compartment are depicted as an oval with dotted lines. The inset in (d) depicts segregation of micro-phase-separated HP1-containing ‘blocks’ that results in the contact enrichment shown by the oval in (c). Micro-phase separation and segregation of the blocks is driven by HP1-mediated ‘bridging’ of H3K9me3-marked nucleosomes within and between clutches.
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References

    1. Saksouk N, Simboeck E, Déjardin J. Constitutive heterochromatin formation and transcription in mammals. Epigenet Chromatin. 2015;8:3. - PMC - PubMed
    1. Singh PB, Belyakin SN, Laktionov PP. Biology and physics of heterochromatin-like domains/complexes. Cells. 2020;9:E1881. - PMC - PubMed
    1. Rao SS, Huntley MH, Durand NC, et al.. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014;159:1665-1680. - PMC - PubMed
    1. Machida S, Takizawa Y, Ishimaru M, et al.. Structural basis of heterochromatin formation by human HP1. Mol Cell. 2018;69:385-397.e8. - PubMed
    1. Strom AR, Emelyanov AV, Mir M, Fyodorov DV, Darzacq X, Karpen GH. Phase separation drives heterochromatin domain formation. Nature. 2017;547:241-245. - PMC - PubMed

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