While the three paralogs show a high degree of homology, they are associated with distinct biological roles ( Canzio et al., 2014 Eissenberg and Elgin, 2014). The mammalian genome contains three HP1 paralogs: HP1α, HP1β, and HP1γ. However, such models raise the fundamental question of how HP1 molecules, which are dynamic on the order of seconds, enable chromatin states that are stable on the order of hours, and further how these states can resist the forces exerted on chromatin in the cell.
The finding that HP1 molecules in these domains exchange within seconds provides some insight into how these domains can be dissolved, because competing molecules would be able to rapidly displace HP1 proteins from DNA ( Cheutin et al., 2003 Festenstein et al., 2003). Yet, these domains can also be rapidly disassembled in response to environmental and developmental cues ( Cheutin and Cavalli, 2012 Dion and Gasser, 2013 Kind et al., 2013).
Heterochromatin domains are typically found to be statically positioned within the nucleus for several hours, held separate from euchromatin ( Gerlich et al., 2003 Marshall et al., 1997).
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In addition to repressing transcription, this type of heterochromatin also plays critical roles in chromosome segregation and in conferring mechanical rigidity to the nucleus ( Allshire and Madhani, 2018 Stephens et al., 2019).įrom investigations of chromatin in cells, it is not immediately obvious how to connect the biophysical properties of HP1 proteins to the diverse roles of HP1-mediated heterochromatin. A highly conserved type of heterochromatin involves the interaction of proteins from the heterochromatin Protein 1 (HP1) family with chromatin that is methylated on histone H3 at lysine 9 ( Bannister et al., 2001 Eissenberg et al., 1990 James and Elgin, 1986 Lachner et al., 2001). Two broad classes of genome compartments are heterochromatin, which contains densely packed DNA regions that are transcriptionally repressed, and euchromatin, which contains physically expanded DNA regions that are transcriptionally active ( Allshire and Madhani, 2018 Heitz, 1928 Saksouk et al., 2015). IntroductionĬompartmentalization of the eukaryotic genome into active and repressed states is critical for the development and maintenance of cell identity ( Becker et al., 2016 Maison and Almouzni, 2004). Our findings suggest a generalizable model for genome organization in which a pool of weakly bound proteins collectively capitalize on the polymer properties of DNA to produce self-organizing domains that are simultaneously resistant to large forces at the mesoscale and susceptible to competition at the molecular scale. Finally, we find that differences in each HP1 paralog’s DNA compaction and phase-separation properties arise from their respective disordered regions. These condensates are resistant to large forces yet can be readily dissolved by HP1β. Using bulk and single-molecule methods, we show that, within phase-separated HP1α-DNA condensates, HP1α acts as a dynamic liquid, while compacted DNA molecules are constrained in local territories. Here, we investigate whether phase-separation by HP1 proteins can explain these biological observations.
In mammals, HP1-mediated heterochromatin forms positionally and mechanically stable genomic domains even though the component HP1 paralogs, HP1α, HP1β, and HP1γ, display rapid on-off dynamics.
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