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How to Rule the Nucleus: Divide Et Impera Available online at www.sciencedirect.com ScienceDirect How to rule the nucleus: divide et impera 1 1 1,2 Irina Solovei , Katharina Thanisch and Yana Feodorova Genome-wide molecular studies have provided new insights conserved and serve as functional platforms for into the organization of nuclear chromatin by revealing the physical interactions between regulatory elements [6– presence of chromatin domains of differing transcriptional 8]. Various other domains, such as lamina-associated activity, frequency of cis-interactions, proximity to scaffolding domains (LADs) [9,10 ,11], nucleolus-associated structures and replication timing. These studies have not only domains (NADs) [12] or pericentromere-associated brought our understanding of genome function to a new level, domains (PADs) [13 ], have been implicated in organiz- but also offered functional insight for many phenomena ing and anchoring the genome within the nucleus. In observed in microscopic studies. In this review, we discuss the cycling cells, genomic regions with time-coordinated major principles of nuclear organization based on the spatial replication form replication domains [14–17]. segregation of euchromatin and heterochromatin, as well as the dynamic genome rearrangements occurring during cell Although the fine details of genome organization and its differentiation and development. We hope to unite the existing functional connections to transcription regulation have molecular and microscopic data on genome organization to get been thoroughly discussed in a plethora of recent reviews a holistic view of the nucleus, and propose a model, in which (e.g., this COCB issue, see also [17–24], it remains a repeat repertoire together with scaffolding structures blueprint challenge to integrate the genomics-based and microsco- the functional nuclear architecture. py-based views into a cohesive concept. Like stepping Addresses back from a pointillist painting, we zoom out to see the 1 Department of Biology II, Ludwig Maximilians University Munich, nucleus in the pattern of its many domains. First, we Grosshadernerstrasse 2, Planegg-Martinsried 82152, Germany define euchromatin (EC) and heterochromatin (HC) 2 Department of Medical Biology, Medical University-Plovdiv, Boulevard domains, discuss how chromatin is spatially organized Vasil Aprilov 15A, Plovdiv 4000, Bulgaria in the nucleus and propose a model in which the repeat Corresponding author: Solovei, Irina ([email protected]) repertoire, together with scaffolding structures, deter- mine chromatin folding. Next, we expand on how EC and HC segregation impacts on chromosome topology Current Opinion in Cell Biology 2016, 40:47–59 and is compatible with the invariant subdivision of chro- This review comes from a themed issue on Cell nucleus matin into TADs. Finally, we ask how chromatin folding Edited by Ulrike Kutay and Orna Cohen-Fix is regulated during differentiation and development, emphasizing the differences between cycling and post- mitotic cells. http://dx.doi.org/10.1016/j.ceb.2016.02.014 Spatial arrangement of EC and HC in the 0955-0674/# 2016 The Authors. Published by Elsevier Ltd. This is an nucleus open access article under the CC BY-NC-ND license (http:// To achieve a functional nuclear architecture, the genome creativecommons.org/licenses/by-nc-nd/4.0/). is segregated into active EC and inactive HC. EC is gene- rich, includes mostly housekeeping genes, and replicates early in S-phase. By contrast, HC is gene-poor, includes Introduction tissue-specific genes, and replicates late in S-phase There is growing evidence that spatial organization is the (Figure 1a; see also [17]). Additionally, EC and HC are key to genome function. In addition to other epigenetic differentially marked by interspersed repetitive factors [1], the arrangement of chromatin within the sequences, which account for up to 45% of the mamma- nucleus is important for transcription regulation and lian genome [25,26]. Short interspersed repetitive for establishing and maintaining cellular identity during sequences (SINEs) reside mostly in gene-rich EC, differentiation. Recent genome-wide molecular studies whereas retrotransposon-related long elements (LINEs) have revealed a variety of distinct chromatin units, or and LTRs locate preferably in HC (Figure 1a). Analysis domains, that build up the interphase nucleus. Chroma- of mammalian genomes by Hi-C revealed that every tin is subdivided into two compartments, A and B, of chromosome can be subdivided into two sets of loci juxtaposed transcriptional activity and apparent spatial forming A and B compartments, within which loci pref- segregation with loci from the same compartment con- erentially interact but avoid interactions with the other tacting each other frequently but avoiding contacts with compartment [2,3 ]. A-compartment and B-compart- loci from the other compartment [2,3 ]. Within compart- ment closely match EC and HC regarding compaction, ments, chromatin is self-organized in topologically asso- gene-richness, expression, replication timing and, con- ciated domains (TADs) [4,5], which are structurally sequently, also repeat repertoire (Figure 1a). www.sciencedirect.com Current Opinion in Cell Biology 2016, 40:47–59 48 Cell nucleus Figure 1 (a) HSA1 (b) SINEs genes n LINEs/LTRs A Hi-C B Euchromatin (EC) early SINE-rich late replication Heterochromatin (HC) LINE-rich n nucleolus LADs human fibroblast human fibroblast mouse neuron human lymphocyte (c) H3K4me3 DAPI H3K27me3 DAPI LINEs, SINEs, DAPI HSA1-5X, HSA17,19,20 ciliate micronucleus hydra chicken human (d) early late Current Opinion in Cell Biology Euchromatic and heterochromatic chromosome regions and their spatial separation in the nucleus. (a) Euchromatin (EC) and heterochromatin (HC) domains revealed by different approaches. Comparison of human chromosome 1 (HSA1) profiles for genes, SINEs, LINEs/LTRs, A/B- compartments [2], replication timing [119], and LADs [9]. EC is gene-dense, SINE-rich and LINE/LTR-poor, corresponds to A-compartment, replicates in the first half of S-phase, and is depleted in LADs. HC shows inverse genomic characteristics, corresponds to B-compartment, and is Current Opinion in Cell Biology 2016, 40:47–59 www.sciencedirect.com Divide et impera Solovei, Thanisch and Feodorova 49 While genome partitioning into chromosomes is crucial (Figure 1b). This view is supported by the polar organiza- for proper cell division, it seems to be dispensable for tion of interphase chromosomes noticed earlier in micro- genome function during interphase. Following mitosis, scopic studies. Regardless of their linear arrangement on chromosomes decondense and form a seamless chromatin the chromosome, gene-poor late-replicating segments lo- mass, in which individual chromosomes are microscopi- calize closer to the nuclear periphery, whereas gene-rich cally indistinguishable, unless visualized with paint early-replicating segments position more centrally [43–46] probes revealing their territorial organization [27]. EC resulting in a clear radial orientation of each chromosome and HC regions of proximal chromosomes form homo- within the nucleus. typic intra-chromosomal and inter-chromosomal contacts thereby ensuring spatial segregation. EC occupies the Which mechanisms could keep EC and HC apart? We nuclear interior, while HC is predominantly associated and others [36,47,48] propose that similarly typed with the periphery and the nucleoli (Figure 1b,c). This sequences exhibit a high affinity to each other thereby nuclear organization has been maintained in eukaryotes driving the separation of the two opposing compartments. over more than 500 million years of evolution (Figure 1d) For example, satellite sequences of centromeric and with only a few exceptions (e.g., [28]). Why is EC and HC subcentromeric regions fuse into chromocenters during segregation crucial for nuclear function? Separation of interphase [13 ,41,48]. Likewise, attraction between dis- silenced from highly expressed regions in the nucleus persed repetitive sequences selectively enriched in EC could be analogous to separating eating from sleeping by and HC, that is, SINEs and LINEs/LTRs, could drive having dedicated rooms. Actively transcribed genes ag- the gathering of homotypic chromatin. The abundance gregate in foci enriched in transcription and splicing and scattering of the repeats along the chromosome axis factors [29–33]. Gene silencing occurs in loci with high enhances the formation of stable contacts between hom- concentration of HC-establishing enzymes, such as onymous repetitive sequences, which serve as nucleation DNMTs, HDACs and HMTs, Polycomb repressive com- points for compartment formation, aptly described by the plexes, as well as HC-binding proteins, such as HP1 and proverb ‘birds of a feather flock together’ [49]. Thus, MECP2 [20,34–39]. Abrogation of segregation leads to mutual attraction of chromatin marked by the same dramatic changes in the developmental program, as was repetitive sequences, enforced by binding of architectural shown recently for Caenorhabditis elegans embryos expres- and epigenetic factors, might serve as a minimal model for sing mutant form of CEC-4, a protein anchoring HC to the separation of EC from HC. the nuclear envelope [40 ]. Segregation by scaffolding While segregation is prominent in terminally differenti- Chromatin segregation is facilitated by binding of HC to ated cells, it has to be re-established after each division in scaffolding structures, the nuclear lamina and the nu- cycling cells.
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