The 3D Genome as Moderator of Chromosomal Communication
2016; Cell Press; Volume: 164; Issue: 6 Linguagem: Inglês
10.1016/j.cell.2016.02.007
ISSN1097-4172
Autores Tópico(s)RNA and protein synthesis mechanisms
ResumoProper expression of genes requires communication with their regulatory elements that can be located elsewhere along the chromosome. The physics of chromatin fibers imposes a range of constraints on such communication. The molecular and biophysical mechanisms by which chromosomal communication is established, or prevented, have become a topic of intense study, and important roles for the spatial organization of chromosomes are being discovered. Here we present a view of the interphase 3D genome characterized by extensive physical compartmentalization and insulation on the one hand and facilitated long-range interactions on the other. We propose the existence of topological machines dedicated to set up and to exploit a 3D genome organization to both promote and censor communication along and between chromosomes. Proper expression of genes requires communication with their regulatory elements that can be located elsewhere along the chromosome. The physics of chromatin fibers imposes a range of constraints on such communication. The molecular and biophysical mechanisms by which chromosomal communication is established, or prevented, have become a topic of intense study, and important roles for the spatial organization of chromosomes are being discovered. Here we present a view of the interphase 3D genome characterized by extensive physical compartmentalization and insulation on the one hand and facilitated long-range interactions on the other. We propose the existence of topological machines dedicated to set up and to exploit a 3D genome organization to both promote and censor communication along and between chromosomes. Communication involves transfer of information from one party to another. This can be achieved in at least two mechanistically distinct ways. First, the parties directly interact, e.g., two or more people directly speaking to each other. Second, information can be transmitted from one location to another via media or intermediates and it is then received by the appropriate partner(s) at their respective locations. For the first mechanism, the two parties need to be physically close, for the second, there needs to be a means to send, transport and receive information from one place to another. Do similar mechanisms operate inside the cell nucleus where genes are regulated by communicating with regulatory elements that can be located elsewhere in the genome? Here we explore the idea that the spatial organization of a genome, and its physical properties, could constitute an effective mechanical communication device. Genes do not work as single, isolated units. Their expression is modulated by regulatory elements that can be located from as little as a kb up to as much as several Mb away, although the precise distance distribution between genes and their regulatory elements is still poorly known (Bickmore, 2013Bickmore W.A. The spatial organization of the human genome.Annu. Rev. Genomics Hum. Genet. 2013; 14: 67-84Crossref PubMed Scopus (141) Google Scholar, Bulger and Groudine, 1999Bulger M. Groudine M. Looping versus linking: toward a model for long-distance gene activation.Genes Dev. 1999; 13: 2465-2477Crossref PubMed Scopus (337) Google Scholar, Carter et al., 2002Carter D. Chakalova L. Osborne C.S. Dai Y.F. Fraser P. Long-range chromatin regulatory interactions in vivo.Nat. Genet. 2002; 32: 623-626Crossref PubMed Scopus (440) Google Scholar, Gibcus and Dekker, 2013Gibcus J.H. Dekker J. The hierarchy of the 3D genome.Mol. 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An example is the case of X chromosome inactivation in female mammals. In this case, the Xist RNA is expressed from one X chromosome only and this RNA spreads along the length of the entire chromosome resulting in gene repression through the Xist-dependent recruitment of a set of silencing complexes (Chu et al., 2015Chu C. Zhang Q.C. da Rocha S.T. Flynn R.A. Bharadwaj M. Calabrese J.M. Magnuson T. Heard E. Chang H.Y. Systematic discovery of Xist RNA binding proteins.Cell. 2015; 161: 404-416Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, Galupa and Heard, 2015Galupa R. Heard E. X-chromosome inactivation: new insights into cis and trans regulation.Curr. Opin. Genet. Dev. 2015; 31: 57-66Crossref PubMed Scopus (58) Google Scholar, Gendrel and Heard, 2014Gendrel A.V. Heard E. Noncoding RNAs and epigenetic mechanisms during X-chromosome inactivation.Annu. Rev. Cell Dev. Biol. 2014; 30: 561-580Crossref PubMed Scopus (88) Google Scholar, Jeon et al., 2012Jeon Y. Sarma K. 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In addition, we mostly discuss chromosome organization and long-range communication in mammalian genomes, even though other organisms including bacteria may employ similar mechanisms. Not all chromosomal communication is for regulating gene expression. An interesting example is intra-chromosomal communication to control somatic recombination in the immunoglobulin loci, such as V(D)J recombination and antibody class switching. During these processes, specific pairs of double-stranded breaks located up to 200 kb apart need to interact to be joined for successful recombination events. Recent studies (Dong et al., 2015Dong J. Panchakshari R.A. Zhang T. Zhang Y. Hu J. Volpi S.A. Meyers R.M. Ho Y.J. Du Z. Robbiani D.F. et al.Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching.Nature. 2015; 525: 134-139Crossref PubMed Scopus (36) Google Scholar, Gostissa et al., 2014Gostissa M. Schwer B. Chang A. Dong J. Meyers R.M. Marecki G.T. Choi V.W. Chiarle R. Zarrin A.A. Alt F.W. IgH class switching exploits a general property of two DNA breaks to be joined in cis over long chromosomal distances.Proc. Natl. Acad. Sci. USA. 2014; 111: 2644-2649Crossref PubMed Google Scholar) have revealed a surprising orientation bias in the IGH class switch recombination process where genomic orientation is preserved in the vast majority of recombination events prior to any further selection. During the process, recombination occurs between recombination sequences that undergo activation-induced cytidine deaminase (AID)-dependent DNA break formation. Interestingly, re-joining of ends is orientation-specific implying long-range communication between the break sites in a manner that maintains the relative orientation of the sites even when they are separated by hundreds of Kb. Thus, communication between two sites where double-stranded breaks are initiated requires not only direct proximity between them, but also preservation of their genomic orientation, pointing to specific processes to facilitate and or mediate their association in a directional manner (discussed below in more detail). With the phenomenon of long-range communication well established, and the roles of chromosome structure and dynamics becoming increasingly clear, many new questions arise: first, how are long-range interactions established, i.e., how do distal elements find one another inside the crowded nucleus? Further, what determines specificity of such interactions and what prevents any of the thousands of active regulatory elements in the genome from inappropriately engaging in contacts with any of the thousands of genes? How do signals spread along chromosomes and how can such spreading be contained to a single chromosome (e.g., X chromosome inactivation)? How is robustness and precision achieved so that important communication is efficiently and rapidly established in most or all cells? Answers to these questions start to emerge now that deeper knowledge is obtained about nuclear organization, the structural compartmentalization of chromosomes, the physical and mechanical properties of chromosomes and their dynamics, and the identification of molecular machines that can actively fold chromosomes to orchestrate and guide long-range communication. Chromosomes are long polymers and many of their structural properties, dynamics and cell-to-cell variability in folding can be understood from their polymer nature. In fact, the polymer state of chromosomes has critical consequences for which pairs of loci have an opportunity to interact, the kinetics of their search for each other, and the number of cells in the population in which interactions occur (Figure 2). To illustrate this we will first explore the scenario in which the 3D genome is determined solely by the physical polymer state of chromosomes. Three physical phenomena are central to our understanding of spatial genomic communication: the short-range character of molecular interactions, the polymeric nature of chromosomes, and the localized dynamics of chromosomal loci (Figure 2). Below we discuss implications of these aspects to genomic communications. Interactions between genomic loci rely on affinity of protein-protein and protein-DNA interactions. Hydrophobic, electrostatic, hydrogen-bonded, and van der Waals in nature, these interactions are either short-range or screened by the high ionic strength of the nucleoplasm. As a result, protein and DNA interphases of a pair of genomic loci can attract each other only if located closer than ∼1–5 nm. The affinity of two DNA-bound proteins will not attract these loci to each other unless they are already very close to each other in space (Figure 2A). Thus formation of most genomic interactions will rely on initially stochastic contacts between genomic loci. Since genomic communications rely on contacts that are already formed, it is the frequency of these contacts that determines possible genomic communications. The polymeric nature of chromosomes makes loci close along the linear genome interact much more frequently than more distant loci or loci located on different chromosomes (trans interactions). Despite this, most interactions are extremely infrequent due to a large volume that is explored by any one locus (Figure 2B). If chromosomes were a melt of polymers in a spherical nucleus of volume V = 300 μm3 (Rnucleus≈4 μm; Milo et al., 2010Milo R. Jorgensen P. Moran U. Weber G. Springer M. BioNumbers--the database of key numbers in molecular and cell biology.Nucleic Acids Res. 2010; 38: D750-D753Crossref PubMed Scopus (0) Google Scholar) two loci from different chromosomes would be in a Hi-C contact (Rc≈100 − 150 nm) with the probability Ptrans≈(Rc/Rnucleus)3∼10−5, i.e., in only a few out of 100,000 cells. In an otherwise unconstrained polymer melt, two loci separated by 10 Mb would be on average R(10 Mb) ∼4 μm apart, as can be estimated assuming fiber parameters from (Naumova et al., 2013Naumova N. Imakaev M. Fudenberg G. Zhan Y. Lajoie B.R. Mirny L.A. Dekker J. Organization of the mitotic chromosome.Science. 2013; 342: 948-953Crossref PubMed Scopus (333) Google Scholar), and interact as infrequently as trans loci. Correspondingly, loci separated by 1 Mb or 100 Kb (R(1 Mb) ≈ 1.4 μm and R(100 Kb) ≈ 0.4 μm) would interact with the probability P(1 Mb)≈(Rc/R)3∼10−3 − 10−4, P(100 Kb) ∼10−2 and thus in a few out of 10,000 and 100 cells, respectively. Two factors would lead to higher contact frequencies: chromosome dynamics and local compaction of chromatin at all levels. The polymeric nature of chromosomes significantly limits mobility of individual loci: moving one locus would require moving its neighbors and their neighbors, etc., which is slow and may be further limited by steric and topological interactions with other nearby chains. As a result, polymers show highly localized mobility with the displacements increasing as time to the power of approximately 1/4 (either due to Rouse diffusion or reptation, compared to normal diffusion where the power is 1/2). Such diffusion has been observed for chromosomal loci in yeast (Hajjoul et al., 2013Hajjoul H. Mathon J. Ranchon H. Goiffon I. Mozziconacci J. Albert B. Carrivain P. Victor J.M. Gadal O. Bystricky K. Bancaud A. 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There are two important consequences of this localized diffusion (Figure 2C): (1) in a given cell, a locus extensively explores its spatial neighborhood (∼150–300 nm in 100 s, 0.5–0.8 μm in 1 hr, and ∼1–1.5 μm in 24 hr, i.e., the length of a typical cell cycle), thus allowing communications between spatially proximal loci; (2) communications at a distance, however, are strongly suppressed since only small spatial distances are explored by a locus during a single cell cycle. Thus loci that happen to be sufficiently close in space upon exit from mitosis can interact, while those that are further apart would not have sufficient time to find each other and will have to wait for the next cell cycle to get a chance of interacting (Strickfaden et al., 2010Strickfaden H. Zunhammer A. van Koningsbruggen S. Köhler D. Cremer T. 4D chromatin dynamics in cycling cells: Theodor Boveri’s hypotheses revisited.Nucleus. 2010; 1: 284-297Crossref PubMed Google Scholar). Even when interacting loci are within a distance that can be spanned within a cell cycle (e.g., ∼1 μm), communication between them would require them first to find each other by this localized diffusive process, which makes time of the response highly variable. Difference in scales between sizes of chromosomal loops and sizes of individual proteins makes it challenging for a single protein to insulate long-range interactions. Even 100 Kb of genomic separation between an enhancer and a promoter implies about ∼2,000–4,000 nm of 10–20 nm fiber that is folded into an area of about ∼300–500 nm in radius. It’s mysterious how 3–5 nm size protein bound somewhere along this chain can significantly influence frequencies of interaction between its monomers (Figure 2D). Recent simulation studies have shown that although formation of a 30 Kb chromatin loop can facilitate intra-loop interactions, insulation of the loop interior from the exterior is very modest with about 30% reduction in the contact frequency Benedetti et al., 2014Benedetti F. Dorier J. Burnier Y. Stasiak A. Models that include supercoiling of topological domains reproduce several known features of interphase chromosomes.Nucleic Acids Res. 2014; 42: 2848-2855Crossref PubMed Scopus (51) Google Scholar, Doyle et al., 2014Doyle B. Fudenberg G. Imakaev M. Mirny L.A. Chromatin loops as allosteric modulators of enhancer-promoter interactions.PLoS Comput. Biol. 2014; 10: e1003867Crossref PubMed Google Scholar). Polymer simulations (Fudenberg et al., 2015Fudenberg, G., Imakaev, M., Lu, C., Goloborodko, A., Adbennur, N., and Mirny, L.A. (2015). Formation of chromosomal domains by loop extrusion. bioRxiv doi: http://dx.doi.org/10.1101/024620.Google Scholar) have also shown that even a bulky protein assembly on a chromatin fiber cannot serve as a reliable insulator providing no insulation beyond the size of the bulky assembly. Similarly, local changes in the flexibility of the chromatin fiber that can be induced by an insulator cannot provide robust insulation between regions distant from the insulator along the genome (Fudenberg et al., 2015Fudenberg, G., Imakaev, M., Lu, C., Goloborodko, A., Adbennur, N., and Mirny, L.A. (2015). Formation of chromosomal domains by loop extrusion. bioRxiv doi: http://dx.doi.org/10.1101/024620.Google Scholar). Taken together, these physical considerations demonstrate that the polymeric nature of chromosomes leads to spatial insulation of distal genomic regions and high cell-to-cell variation of their contacts, while at the same time allowing frequent contacts between genomically proximal regions. For small genomes such as yeast and C. elegans, this may be sufficient to ensure appropriate gene regulation. However, for larger genomes this will become a highly stochastic process leading to tremendous cell-to-cell variation in gene expression. Hence, in order to achieve robust, precise and reproducible cell type-specific gene expression patterns across the genome, additional layers of chromosome organization are required so that communications between more distal regions can be actively facilitated, while interactions between more proximal loci can be moderated both ways: they can be facilitated in some cases but may need to be actively prevented (insulated) in other cases to prevent inappropriate gene—regulatory element interactions. It is now becoming clear that cells have evolved mechanisms to compartmentalize chromosomes at all scales, which allow more precise control of interactions between some sets of loci, while preventing others in the majority of cells. Years of microscopic observations and 3C-based studies have revealed that the spatial organization of the genome is not just a melt of otherwise uniform polymers: chromosomes are characterized by structural compartmentalization at many levels (Bickmore, 2013Bickmore W.A. The spatial organization of the human genome.Annu. Rev. Genomics Hum. Genet. 2013; 14: 67-84Crossref PubMed Scopus (141) Google Scholar, Bickmore and van Steensel, 2013Bickmore W.A. van Steensel B. Genome architecture: domain organization of interphase chromosomes.Cell. 2013; 152: 1270-1284Abstract Full Text Full Text PDF PubMed Scopus (336) Google Scholar, Bouwman and de Laat, 2015Bouwman B.A. de Laat W. Getting the genome in shape: the formation of loops, domains and compartments.Genome Biol. 2015; 16: 154Crossref PubMed Scopus (42) Google Scholar, Gibcus and Dekker, 2013Gibcus J.H. Dekker J. The hierarchy of the 3D genome.Mol. 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Within territories chromosomes are compartmentalized in different types of sub-chromosomal domains. At the scale of several Mb, animal chromosomes show characteristics of space-filling polymers, i.e., continuous genomic regions occupy continuous chromosomal volumes (Shopland et al., 2006Shopland L.S. Lynch C.R. Peterson K.A. Thornton K. Kepper N. Hase Jv. Stein S. Vincent S. Molloy K.R. Kreth G. et al.Folding and organization of a contiguous chromosome region according to the gene distribution pattern in primary genomic sequence.J. Cell Biol. 2006; 174: 27-38Crossref PubMed Scopus (0) Google Scholar). This space-filling character of 0.1–10 Mb of chromosomes is evident from microscopy data that show linear (or sub-linear) scaling of occupied volume with the length s of a stained genomic region (V(s) ∼sα α ≤ 1) and from the scaling R(s) ∼s1/3 of the spatial distance between pairs with their genomic separation s (Rosa and Everaers, 2008Rosa A. Everaers R. Structure and dynamics of interphase chro
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