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      Phase separation drives heterochromatin domain formation

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      Nature
      Springer Nature

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          Abstract

          Constitutive heterochromatin is an important component of eukaryotic genomes that has essential roles in nuclear architecture, DNA repair and genome stability, and silencing of transposon and gene expression. Heterochromatin is highly enriched for repetitive sequences, and is defined epigenetically by methylation of histone H3 at lysine 9 and recruitment of its binding partner heterochromatin protein 1 (HP1). A prevalent view of heterochromatic silencing is that these and associated factors lead to chromatin compaction, resulting in steric exclusion of regulatory proteins such as RNA polymerase from the underlying DNA. However, compaction alone does not account for the formation of distinct, multi-chromosomal, membrane-less heterochromatin domains within the nucleus, fast diffusion of proteins inside the domain, and other dynamic features of heterochromatin. Here we present data that support an alternative hypothesis: that the formation of heterochromatin domains is mediated by phase separation, a phenomenon that gives rise to diverse non-membrane-bound nuclear, cytoplasmic and extracellular compartments. We show that Drosophila HP1a protein undergoes liquid–liquid demixing in vitro, and nucleates into foci that display liquid properties during the first stages of heterochromatin domain formation in early Drosophila embryos. Furthermore, in both Drosophila and mammalian cells, heterochromatin domains exhibit dynamics that are characteristic of liquid phase-separation, including sensitivity to the disruption of weak hydrophobic interactions, and reduced diffusion, increased coordinated movement and inert probe exclusion at the domain boundary. We conclude that heterochromatic domains form via phase separation, and mature into a structure that includes liquid and stable compartments. We propose that emergent biophysical properties associated with phase-separated systems are critical to understanding the unusual behaviours of heterochromatin, and how chromatin domains in general regulate essential nuclear functions.

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          Most cited references17

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          Sequence complexity of disordered protein.

          Intrinsic disorder refers to segments or to whole proteins that fail to self-fold into fixed 3D structure, with such disorder sometimes existing in the native state. Here we report data on the relationships among intrinsic disorder, sequence complexity as measured by Shannon's entropy, and amino acid composition. Intrinsic disorder identified in protein crystal structures, and by nuclear magnetic resonance, circular dichroism, and prediction from amino acid sequence, all exhibit similar complexity distributions that are shifted to lower values compared to, but significantly overlapping with, the distribution for ordered proteins. Compared to sequences from ordered proteins, these variously characterized intrinsically disordered segments and proteins, and also a collection of low-complexity sequences, typically have obviously higher levels of protein-specific subsets of the following amino acids: R, K, E, P, and S, and lower levels of subsets of the following: C, W, Y, I, and V. The Swiss Protein database of sequences exhibits significantly higher amounts of both low-complexity and predicted-to-be-disordered segments as compared to a non-redundant set of sequences from the Protein Data Bank, providing additional data that nature is richer in disordered and low-complexity segments compared to the commonness of these features in the set of structurally characterized proteins.
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            The permeability barrier of nuclear pore complexes appears to operate via hydrophobic exclusion.

            Nuclear pore complexes (NPCs) restrict the nucleocytoplasmic flux of most macromolecules, but permit facilitated passage of nuclear transport receptors and their cargo complexes. We found that a simple hydrophobic interaction column can mimic the selectivity of NPCs surprisingly well and that nuclear transport receptors appear to be the most hydrophobic soluble proteins. This suggests that surface hydrophobicity represents a major sorting criterion of NPCs. The rate of NPC passage of cargo-receptor complexes is, however, not dominated just by properties of the receptors. We found that large cargo domains drastically hinder NPC passage and require more than one receptor molecule for rapid translocation. This argues against a rigid translocation channel and instead suggests that NPC passage involves a partitioning of the entire translocating species into a hydrophobic phase, whereby the receptor:cargo ratio determines the solubility in that permeability barrier. Finally, we show that interfering with hydrophobic interactions causes a reversible collapse of the permeability barrier of NPCs, which is consistent with the assumption that the barrier is formed by phenylalanine-rich nucleoporin repeats that attract each other through hydrophobic interactions.
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              Non-globular domains in protein sequences: automated segmentation using complexity measures.

              Computational methods based on mathematically-defined measures of compositional complexity have been developed to distinguish globular and non-globular regions of protein sequences. Compact globular structures in protein molecules are shown to be determined by amino acid sequences of high informational complexity. Sequences of known crystal structure in the Brookhaven Protein Data Bank differ only slightly from randomly shuffled sequences in the distribution of statistical properties such as local compositional complexity. In contrast, in the much larger body of deduced sequences in the SWISS-PROT database, approximately one quarter of the residues occur in segments of non-randomly low complexity and approximately half of the entries contain at least one such segment. Sequences of proteins with known, physicochemically-defined non-globular regions have been analyzed, including collagens, different classes of coiled-coil proteins, elastins, histones, non-histone proteins, mucins, proteoglycan core proteins and proteins containing long single solvent-exposed alpha-helices. The SEG algorithm provides an effective general method for partitioning the globular and non-globular regions of these sequences fully automatically. This method is also facilitating the discovery of new classes of long, non-globular sequence segments, as illustrated by the example of the human CAN gene product involved in tumor induction.
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                Author and article information

                Journal
                Nature
                Nature
                Springer Nature
                0028-0836
                1476-4687
                June 21 2017
                June 21 2017
                :
                :
                Article
                10.1038/nature22989
                28636597
                a6507ff6-a8f3-41ce-b161-fd939f87c89f
                © 2017
                History

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