Biology and physics of heterochromatin-likedomains/complexes

The hallmarks of constitutive heterochromatin, HP1 and H3K9me2/3, assemble heterochromatin- like domains/complexes outside canonical constitutively heterochromatic territories where they regulate chromatin-templated processes. Domains are more than 100kb in size; complexes less than 100kb. They are present in the genomes of organisms ranging from fission yeast to man, with an expansion in size and number in mammals. Some of the likely functions of the domains/complexes include silencing of the donor mating type region in fission yeast, regulation of mammalian imprinted genes and the phylotypic progression during vertebrate development. Far cis - and trans -contacts between micro-phase separated domains/complexes in mammalian nuclei contribute to the emergence of epigenetic compartmental domains (ECDs) detected in Hi-C maps. We speculate that a thermodynamic description of micro-phase separation of heterochromatin- like domains/complexes will require a gestalt shift away from the monomer as the “ unit of incompatibility ”, where it is the choice of monomer that determines the sign and magnitude of the Flory-Huggins parameter, χ. Instead, a more dynamic structure, the oligo-nucleosomal “clutch”, consisting of between 2 to 10 nucleosomes is both the long sought-after secondary structure of chromatin and its unit of incompatibility. Based on this assumption we present a simple theoretical framework that enables an estimation of χ for domains/complexes flanked by euchromatin and thereby an indication of their tendency to phase separate. The degree of phase separation is specified by χN, where N is the number of “clutches” in a domain/complex. Our approach may provide an additional tool for understanding the biophysics of the 3D genome.