OVERWIEW OF THREE DIMENSIONAL GENOM ORGANIZATION

Yıl 2019, Cilt: 20 Sayı: 1, 208 - 216, 27.08.2019

Evrim Suna Arıkan Terzi , Müjgan Özdemir Erdoğan , Mustafa Solak

https://doi.org/10.18229/kocatepetip.450681

Öz

A fundamental property of genomes is their topological organization in the cell nucleus. “Chromosome territories” refer to the use of certain regions of the nucleus by a specific chromosomes. It is determined that, chromosomes are not arranged randomly in the cell space and many genes in the genom occupy preferred areas. The organization of chromosomal domains are associated to gene density and size. In this case, it has been reported that gene-rich chromosomes prefer interior positions and that gene-poor chromosomes prefer peripheral positions. Chromosomal domains are also dynamic structures, so genes can be displaced from the periphery to the interior position when opened.

It is known that the spatial organization of the human genome plays an important role in the transcriptional control of genes. Based on studies of promoter and enhancer interactions by DNA looping, it is clear that gene expression is facilitated and regulated through contacts of distal chromatin contacts. The primary research topics are how regulatory DNA elements and genes are wired to properly execute cell-specific transcription regulatory programs. Genetic experiments have uncovered three rules of enhancer–promoter engagement: linear proximity matters, enhancer and promoter compatibility and some sequences exist that can block enhancer activity. To understand the molecular mechanisms behind these rules, we need to know how regulatory sites exert activities over distance.

It is found that a given mammalian cell type contains thousands or more regulatory sites. With 200 different cell types, this confirms that our genome harbours a complex regulatory landscape. From linear DNA to the three dimensional nucleus, chromatin organization is well characterized on both the small scale and the very large scale; however, our understanding of the intermediate levels of chromatin organization remains limited. With the advent of chromosome conformation capture (3C) technologies tremendous progress in our understanding of three dimensional chromatin organization of interphase nucleus has been made.

In this review, it is mentioned about spatial organization of genom, some interactions in this organisation and some actual studies in recent years.

Anahtar Kelimeler

Three dimensional genome, Chromosome territories, Enhancer

ÜÇ BOYUTLU GENOM ORGANİZASYONUNA GENEL BAKIŞ

Öz

Genomların temel özelliği hücre çekirdeğindeki üç boyutlu topolojik organizasyonudur. “Kromozom alanları” terimi nükleusun belli bölgelerinin belli kromozomlar tarafından kullanılmasını ifade etmektedir. Yani kromozomların nüklear boşlukta rastgele düzenlenmediği, genom içindeki bazı genlerin tercih ettikleri bölgeleri işgal ettikleri tespit edilmiştir. Kromozom alanlarının organizasyonu gen yoğunluğu ve boyutu ile ilişkilidir. Bu durumda gen bakımından zengin kromozomların interior pozisyonları, gen bakımından zayıf kromozomların perifer pozisyonları tercih ettiği rapor edilmiştir. Kromozom alanları ayrıca dinamik yapılardır böylece genler açılacağı zaman periferden interior pozisyona doğru yer değiştirebilirler.

İnsan genomunun mekansal organizasyonunun genlerin transkripsiyonel kontrolünde önemli bir rol oynadığı bilinmektedir. DNA ilmeklenmesiyle promotör ve enhansır etkileşimleri temelli çalışmalar gen ekspresyonunun uzaktaki kromatin temaslarıyla düzenlendiğini göstermiştir. Düzenleyici DNA elemanları ve genlerin hücreye spesifik transkripsiyon düzenleyici programları nasıl yürüttüğü başta gelen araştırma konularındandır. Genetik çalışmalar enhansır promotör birlikteliğinin üç kuralı etrafında tamamlanır: Doğrusal yakınlık durumları, enhansır promotör uyumu ve enhansır aktivitesini bloklayabilen sekansların varlığı. Bu kuralların arkasında yatan moleküler mekanizmaları anlamak için regülatör bölgelerin uzak mesafelerde nasıl faaliyet gösterdiğini bilmeye ihtiyacımız vardır.

Herhangi bir hücre tipinin binlerce ya da daha fazla düzenleyici bölge içerdiği bulunmuştur. 200 hücre tipi göz önüne alındığında insan genomunun karmaşık bir düzenleyici sistem olarak çalıştığı görülmektedir. Doğrusal DNA’dan üç boyutlu nükleusa kadar kromatin organizasyonu küçük ve büyük ölçekte çok iyi karakterize edilmiştir ancak ara seviyelerdeki kromatin organizasyonu hakkında bilgilerimiz hala sınırlıdır. Kromozom konformasyonunu yakalama (3C) teknolojilerinin gelişmesi interfaz nükleusunun üç boyutlu kromatin organizasyonuna yeni bakış açısı getirmiştir.

Bu derlemede, genomun mekânsal organizasyonundan, bu organizasyondaki bazı etkileşimlerden ve son yıllarda yapılan bazı çalışmalardan bahsedilmiştir.

Anahtar Kelimeler

3D genom, Kromozom alanları, Enhansır, İzolatör

Kaynakça

• 1- Bickmore W. The spatial organization of the human genome. Annual review of genomics and human genetics. 2013;(14):67–84.2- Luger K, Mäder AW, Richmond, RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 1997;(389):251–260. 3- Robert L. Nussbaum, Roderick R Mclnnes, Huntington F Willard, Thomson-Thompson Tıbbi Genetik Kitabı 2005, Güneş Kitabevi, Ankara4- Schleif R. DNA looping. Annual review of biochemistry. 1992;(61):199–223.5- Cavalli G, Misteli T. Functional implications of genome topology. Nat Struct and Mol Biol 2013; (20):290–299. 6- Feng S, Cokus SJ, Schubert V, Zhai J, Pellegrini M, Jacobsen SE. Genome-wide Hi-C analyses in wild-type and mutants reveal high-resolution chromatin interactions in Arabidopsis. Mol Cell 2014;(55):694–707.7- Sun L, Yu R and Dang W. Chromatin Architectural Changes during Cellular Senescence and Aging. Genes 2018;(9):211; Doi:10.3390/genes90402118- Kharchenko PV, Alekseyenko AA, Schwartz YB, et al. Comprehensive analysis of the chromatin landscape in Drosophila melanogaster. Nature 2011;(471):480–485.9- Gierman HJ, Indemans MHG, Koster J et al. Domain-wide regulation of gene expression in the human genome. Genome Res 2007;(17):1286–1295.10- Lanctot C, Cheutin T, Cremer M, Cavalli G, Cremer T. Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nat Rev Genet 2007;(8):104–115.11- Misteli T. Beyond the sequence: Cellular organization of genome function. Cell 2007;(128):787–800.12- Rajapakse I, Groudine M. On emerging nuclear order. J Cell Biol 2011;(192):711–721.13- Cremer T, Cremer M. Chromosomal territories. Cold Spring Harb Perspect Biol 2010;(2):a003889. doi:10.1101/cshperspect.a003889 14- Dekker J, Rippe K, Dekker M, Kleckner N. Capturing chromosome conformation. Science 2002;(295):1306–131115- Lieberman-Aiden E, van Berkum NL, Williams L, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 2009;(326):289–293. 16- van Berkum NL, Lieberman-Aiden E, Williams L, et al. Hi-C: a method to study the three-dimensional architecture of genomes. J Vis Exp 2010;May 6;(39). pii: 1869. doi: 10.3791/1869.17- Dekker J, Marti-Renom MA, Mirny LA. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat Rev Genet 2013;(14):390–403. 18- Naumova N, Imakaev M, Fudenberg G, et al. Organization of the mitotic chromosome. Science 2013;(342):948–953. 19- Serizay J, Ahringer J. Genome organization at different scales: nature, formation and function. Curr Opin Cell Biol 2018;(52):145–153 20- Meaburn KJ, Misteli T. Cell biology: chromosome territories. Nature 2007; 445(7126):379-781.21- Mayer R, Brero A, von Hase J, Schroeder T, Cremer T, Dietzel S. Common themes and cell type specific variations of higher order chromatin arrangements in the mouse. BMC Cell Biol. 2005;(6):44. 22- Tanabe H, Habermann FA, Solovei I, Cremer M, Cremer T. Non-random radial arrangements of interphase chromosome territories: evolutionary considerations and functional implications. Mutat Res 2002; 504(1-2):37-45. 23- Sun HB, Shen J, Yokota H. Size-dependent positioning of human chromosomes in interphase nuclei. Biophys J 2000; 79(1):184-90.24- Chuang C, Carpenter AE, Fuchsova B, Johnson T, de Lanerolle P, Belmont AS. Long-range directional movement of an interphase chromosome site. Curr Biol 2006; 16(8):825-31. 25- Galiová G, Bártová E, and Kozubek S. Nuclear topography of beta-like globin gene cluster in IL-3-stimulated human leukemic K-562 cells. Blood Cells Mol Dis 2006;33(1):4-14. 26- Foster HA, Bridger JM. The genome and the nucleus: a marriage made by evolution. Genome organisation and nuclear architecture. Chromosoma 2005;114(4):212-29. 27- Orsztynowicz M, Lechniak D, Pawlak P, et al. Changes in chromosome territory position within the nucleus reflect alternations in gene expression related to embryonic lineage specification. PLoS ONE 2017;(12)e0182398. [28- Eils R, Dietzel S, Bertin E, Schrock E. Three-dimensional reconstruction of painted human interphase chromosomes: Active and inactive X chromosome territories have similar volumes but differ in shape and surface structure. J Cell Biol 1996;(135):1427–1440. 29- Croft JA, Bridger JM, Boyle S, Perry P, Teague P, Bickmore WA. Differences in the localization and morphology of chromosomes in the human nucleus. J Cell Biol 1999;(145):1119- 1131.30- Gibcus JH, Samejima K, Goloborodko A, et al. A pathway for mitotic chromosome formation. Science 2018:6135.31- Sexton T, Yaffe E, Kenigsberg E et al. Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 2012;(148):458–472.32- Splinter E, de Laat W. The complex transcription regulatory landscape of our genome: control in three dimensions. EMBO J 2011;(30):4345–4355.33- Williams A, Spilianakis CG, Flavell RA. Interchromosomal association and gene regulation in trans. Trends Genet 2010;(26):188–197.34- Yu H, Zhu S, Zhou B, Xue H, Han JD. Inferring causal relationships among different histone modifications and gene expression. Genome Res 2008;(18):1314–1324.35- Bock C, Lengauer T. Computational epigenetics. Bioinformatics 2008;(24):1–10.36- Roy S, Ernst J, Kharchenko PV, et al. Identification of functional elements and regulatory circuits by Drosophila modENCODE. Science 2010;(330):1787–1797.37- Gerstein MB, Lu ZJ, Van Nostrand EL, et al. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project. Science 2010;(330): 1775–1787.38- Spitz F, Gonzalez F, Duboule D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 2003;(113): 405–41739- Denholtz M, Plath K. Pluripotency in 3D: Genome organization in pluripotent cells Curr Opin Cell Biol. 2012;December;24(6):793–801. 40- Hou C, Corces VG. Throwing transcription for a loop: expression of the genome in the 3D nucleus. Chromosoma 2012;(121):107–116.41- Tan-Wong SM, Wijayatilake HD, Proudfoot NJ. Gene loops function to maintain transcriptional memory through interaction with the nuclear pore complex. Genes 2009;(23):2610–2624. 42- Tan-Wong SM, J B. Zaugg JB, Camblong J. et al. Gene loops enhance transcriptional directionality. Science 338, 671–675 (2012).43- Tolhuis B, Palstra RJ, Splinter E, Grosveld F, de Laat, W. Looping and interaction between hypersensitive sites in the active beta-globin locus. Mol Cell 2002;(10):1453–1465.44- Breiling A, Turner BM, Bianchi ME, Orlando V. General transcription factors bind promoters repressed by Polycomb group proteins. Nature 2001;(12):651–655 45- Yang J, Corces VG. Insulators, long-range interactions, and genome function. Curr Opin Genet Dev 2012;(22):86–92.46- de Villiers J, Olson L, Banerji J, Schaffner W. Analysis of the transcriptional enhancer effect. Cold Spring Harb Symp Quant Biol 1983;47(Part 2): 911–919.47- Dillon N, Trimborn T, Strouboulis J, Fraser P, Grosveld F. The effect of distance on long-range chromatin interactions. Mol Cell 1997;(1):131–139.48- de Laat W, Grosveld F. Spatial organization of gene expression: the active chromatin hub. Chromosome Res 2003;(11):447–459.49- Splinter E, Heath H, Kooren J, et al. CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus. Genes Dev 2006;(20): 2349–2354.50- Cajiao I, Zhang A, Yoo EJ, Cooke NE, Liebhaber SA. Bystander gene activation by a locus control region. EMBO J 2004;(23):3854–3863.51- Lower KM, Hughes JR, De Gobbi M, et al. Adventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition. Proc Natl Acad Sci USA 2006;(106):21771–21776.52- Dixon J, Selvaraj S, Yue F, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 2012;(485):376–380.53- Nora E, Lajoie B, Schulz E, et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature. 2012;(485):381–385.54- Phillips-Cremins JE, Sauria ME,Sanyal A, et al. Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment Cell 2013;(153):1281–1295.55- Rao SS, Huntley MH, Durand NC et al. A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping. Cell 2015;(162)3:687-688. 56- Jin F, Li Y, Dixon JR, et al. A high-resolution map of the three-dimensional chromatin interactome in human cells. Nature 2013;(503):290–294.57- Flavahan WA, Drier Y, Liau BB, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2015;529(7584):110-114 58- Bell AC, West AG, Felsenfeld G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell 1999;(98):387–396.59- Guelen L, Pagie L, Brasset E, et al. Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions. Nature 2008;(453):948–951.60- Filippova GN, Cheng MK, Moore JM, Tet al. Boundaries between chromosomal domains of X inactivation and escape bind CTCF and lack CpG methylation during early development. Dev Cell 2005;(8):31–42.61- Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM. CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 2000;(405):486–489.62- Barski A, Cuddapah S, Cui K, et al. High-resolution profiling of histone methylations in the human genome. Cell 2007;(129):823–837.63- Kunarso G, Chia NY, Jeyakani J, et al. Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat Genet 2010;(42): 631–634.64- Xie X, Mikkelsen TS, Gnirke A, Lindblad-Toh K, Kellis M, Lander ES. Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites. Proc Natl Acad Sci USA 2007;(104): 7145–7150.65- Parelho V, Hadjur S, Spivakov M, et al. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell 2008;(132): 422–433.66- Wendt KS, Yoshida K, Itoh T, et al. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature 2008;(451):796–801.67- Smith JS, Savage KI, Thompson A, Mills KI. Loss of Function Cohesin Complex Gene Mutations Create Neomorphic Cell States Advantageous to Oncogenesis Blood 2016;(128):1564-1565.68- Schmidt D, Schwalie PC, Wilson MD, et al. Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages. Cell. 2012;(148):335–348. 69- International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 2004;(431):931–945. 70- Eagen KP. Principles of Chromosome Architecture Revealed by Hi-C. Trends Biochem Sci 2018;(43)No.6: 469-478.71- Aranda S, Mas G, and Di Croce L. Regulation of gene transcription by Polycomb proteins Sci Adv 2015;(1):no. 11, e1500737. doi: 10.1126/sciadv.150073772- Bodnar MS, Spector DL. Chromatin Meets Its Organizers. Cell 2013;153(6):1187-1189. 73- Bernardi G. Chromosome Architecture and Genome Organization. PLoS ONE. 2015;10(11):e0143739. doi:10.1371/journal.pone.0143739.