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      HP1 drives de novo 3D genome reorganization in early Drosophila embryos

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          Abstract

          Fundamental features of 3D genome organization are established de novo in the early embryo, including clustering of pericentromeric regions, the folding of chromosome arms and the segregation of chromosomes into active (A-) and inactive (B-) compartments. However, the molecular mechanisms that drive de novo organization remain unknown 1, 2 . Here, by combining chromosome conformation capture (Hi-C), chromatin immunoprecipitation with high-throughput sequencing (ChIP–seq), 3D DNA fluorescence in situ hybridization (3D DNA FISH) and polymer simulations, we show that heterochromatin protein 1a (HP1a) is essential for de novo 3D genome organization during Drosophila early development. The binding of HP1a at pericentromeric heterochromatin is required to establish clustering of pericentromeric regions. Moreover, HP1a binding within chromosome arms is responsible for overall chromosome folding and has an important role in the formation of B-compartment regions. However, depletion of HP1a does not affect the A-compartment, which suggests that a different molecular mechanism segregates active chromosome regions. Our work identifies HP1a as an epigenetic regulator that is involved in establishing the global structure of the genome in the early embryo.

          Abstract

          The heterochromatin protein HP1 has an essential role in establishing several features of the 3D nuclear organization of the genome during early embryonic development in Drosophila.

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          Comprehensive mapping of long-range interactions reveals folding principles of the human genome.

          We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.
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            Phase separation drives heterochromatin domain formation

            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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              Liquid droplet formation by HP1α suggests a role for phase separation in heterochromatin

              Gene silencing by heterochromatin is proposed to occur in part from the ability of HP1 proteins to spread across large regions of the genome, compact the underlying chromatin and recruit repressive activities 1–3 . Here we identify a new property of the human HP1α protein: the ability to form phase-separated droplets. While unmodified HP1α is soluble, either phosphorylation of its N-terminal extension or DNA binding promotes the formation of phase-separated droplets. Phosphorylation driven phase-separation can be promoted or reversed by specific HP1α ligands. Known components of heterochromatin such as nucleosomes and DNA preferentially partition into the HP1α droplets but other molecules such as the transcription factor TFIIB show no preference. Using single-molecule DNA curtains we find that unmodified and phosphorylated HP1α induce rapid compaction of DNA strands into puncta, though with different characteristics. We show by direct protein delivery into mammalian cells that an HP1α mutant incapable of phase separation in vitro forms smaller and fewer nuclear puncta than phosphorylated HP1α. These findings suggest that heterochromatin mediated gene silencing may occur in part through sequestration of compacted chromatin in phase-separated HP1 droplets, which are dissolved or formed by specific ligands based on nuclear context.
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                Author and article information

                Contributors
                luca.giorgetti@fmi.ch
                iovino@ie-freiburg.mpg.de
                Journal
                Nature
                Nature
                Nature
                Nature Publishing Group UK (London )
                0028-0836
                1476-4687
                14 April 2021
                14 April 2021
                2021
                : 593
                : 7858
                : 289-293
                Affiliations
                [1 ]GRID grid.429509.3, ISNI 0000 0004 0491 4256, Max Planck Institute of Immunobiology and Epigenetics, ; Freiburg im Breisgau, Germany
                [2 ]GRID grid.5963.9, Albert-Ludwigs-Universität Freiburg, ; Freiburg im Breisgau, Germany
                [3 ]GRID grid.482245.d, ISNI 0000 0001 2110 3787, Friedrich Miescher Institute for Biomedical Research, ; Basel, Switzerland
                [4 ]GRID grid.6612.3, ISNI 0000 0004 1937 0642, University of Basel, ; Basel, Switzerland
                [5 ]GRID grid.5963.9, CIBSS – Centre for Integrative Biological Signalling Studies, , University of Freiburg, ; Freiburg im Breisgau, Germany
                [6 ]GRID grid.4708.b, ISNI 0000 0004 1757 2822, Università degli Studi di Milano and INFN, ; Milan, Italy
                Author information
                http://orcid.org/0000-0002-0324-0902
                http://orcid.org/0000-0001-7702-6207
                http://orcid.org/0000-0002-3625-0939
                http://orcid.org/0000-0002-9664-9087
                http://orcid.org/0000-0002-3335-7618
                Article
                3460
                10.1038/s41586-021-03460-z
                8116211
                33854237
                a057074a-348b-4604-9dcd-b36b38f792f6
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 November 2019
                : 16 March 2021
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                © The Author(s), under exclusive licence to Springer Nature Limited 2021

                Uncategorized
                embryogenesis,epigenetic memory,epigenetics,chromatin,nuclear organization
                Uncategorized
                embryogenesis, epigenetic memory, epigenetics, chromatin, nuclear organization

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