起航三维基因组学研究
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摘要
人类基因组测序完成已有十多年.但是,基因组信息如何指导基因在特定空间和时间表达的机理仍有待阐明."结构决定功能"是认识自然规律中的一个共识.在生物学中,这一共识不仅适用于RNA、蛋白质等小规模的有机分子,同样也应该适用于全基因组这样的DNA大分子.最近的研究表明,基因组的三维空间结构对基因组的表达、调控等功能有重要的影响.因此,研究全基因组的三维空间结构和功能成为基因组学一个新发展趋势.基因组三维空间结构与功能的研究简称三维基因组学,是指在考虑基因组序列、基因结构及其调控元件的同时,对基因组序列在细胞核内的三维空间结构,及其对基因转录、复制、修复和调控等生物过程中功能的研究.随着大规模基因组测序技术的发展,我们已经拥有研究三维基因组的相关技术如ChIA-PET和Hi-C.初步的ChIA-PET和Hi-C数据分析展示了基因组三维空间结构对基因组功能的意义,为进一步研究基因组三维空间结构和功能提供了基础.本文总结了三维基因组学研究的发展,概括了三维基因组学研究中的问题和目前的进展,并讨论了可能的应用前景.登高更见远,期待三维基因组学研究将深化对生命现象和规律的认识,为基础生物学发展带来新契机、为更进一步推动生物医学及农业应用打下坚实的基础.
It is already more than 10 years after the completion of Human Genome Project. However, the mechanism about how genomic information guides the gene expression in a particular space and time remains to be elucidated. "Structure determines function" is a consensus that we understand the laws of nature. In biology, this consensus is not only applicable to RNA, protein and other small-scale organic molecules; the same should also apply to macromolecules such as the entire DNA composition of the whole genome. Recent studies have shown that three-dimensional(3D) structure of the genome has an important impact on the regulation of gene transcription and other nuclear functions. Therefore, the study of the 3D structure and function of the whole genome(referred to as 3D genomics) has become a new trend of development in genomics. With the consideration of the genome sequence, gene structure and regulatory elements at the same time, 3D genomics studies the 3D structure of the genome in the nucleus, and its impact on gene transcription, replication, repair, regulation and others biological processes. With the progress of large-scale genome sequencing technology, we already have the relevant technologies such as ChIA-PET and Hi-C for the study of 3D genomics. Preliminary results showed the influence of genome 3D structures to genome functions, which provides the basis for further study of genome structure and function in the spatial nuclear space. This paper summarizes the emergence of 3D genomics, lists the issues and the current progress in this new field, and discusses possible applications of 3D genomics to human health and agriculture researches. We anticipate that 3D genomics will provide novel insights into the genome regulatory functions and provide new opportunities of improving human life qualities.
It is already more than 10 years after the completion of Human Genome Project. However, the mechanism about how genomic information guides the gene expression in a particular space and time remains to be elucidated. "Structure determines function" is a consensus that we understand the laws of nature. In biology, this consensus is not only applicable to RNA, protein and other small-scale organic molecules; the same should also apply to macromolecules such as the entire DNA composition of the whole genome. Recent studies have shown that three-dimensional(3D) structure of the genome has an important impact on the regulation of gene transcription and other nuclear functions. Therefore, the study of the 3D structure and function of the whole genome(referred to as 3D genomics) has become a new trend of development in genomics. With the consideration of the genome sequence, gene structure and regulatory elements at the same time, 3D genomics studies the 3D structure of the genome in the nucleus, and its impact on gene transcription, replication, repair, regulation and others biological processes. With the progress of large-scale genome sequencing technology, we already have the relevant technologies such as ChIA-PET and Hi-C for the study of 3D genomics. Preliminary results showed the influence of genome 3D structures to genome functions, which provides the basis for further study of genome structure and function in the spatial nuclear space. This paper summarizes the emergence of 3D genomics, lists the issues and the current progress in this new field, and discusses possible applications of 3D genomics to human health and agriculture researches. We anticipate that 3D genomics will provide novel insights into the genome regulatory functions and provide new opportunities of improving human life qualities.
引文
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2 The ENCODE Project Consortium.An integrated encyclopedia of DNA elements in the human genome.Nature,2012,489:57–74
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10 Zhao Z,Tavoosidana G,Sjlinder M,et al.Circular chromosome conformation capture(4C)uncovers extensive networks of epigenetically regulated intra-and interchromosomal interactions.Nat Genet,2006,38:1341–1347
11 Dostie J,Richmond T A,Arnaout R A,et al.Chromosome Conformation Capture Carbon Copy(5C):A massively parallel solution for mapping interactions between genomic elements.Genome Res,2006,16:1299–1309
12 Lieberman-Aiden E,van Berkum N L,Williams L,et al.Comprehensive mapping of long-range interactions reveals folding principles of the human genome.Science,2009,326:289–293
13 Kieffer-Kwon K R,Tang Z,Mathe E,et al.CTCF-mediated functional chromatin interactome in pluripotent cells.Nat Genet,2011,43:630–638
14 Handoko L,Xu H,Li G,et al.Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations.Nature,2013,504:306–310
15 Kieffer-Kwon K R,Tang Z,Mathe E,et al.Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.Cell,2013,155:1507–1520
16 DeMare L E,Leng J,Cotney J,et al.The genomic landscape of cohesin-associated chromatin interactions.Genome Res,2013,23:1224–1234
17 Chepelev I,Wei G,Wangsa D,et al.Characterization of genome-wide enhancer-promoter interactions reveals co-expression of interacting genes and modes of higher order chromatin organization.Cell Res,2012,22:490–503
18 Zhang Y,McCord R P,Ho Y J,et al.Spatial organization of the mouse genome and its role in recurrent chromosomal translocations.Cell,2012,148:908–921
19 Burton J N,Adey A,Patwardhan R P,et al.Chromosome-scale scaffolding of de novo genome assemblies based on chromatin interactions.Nat Biotechnol,2013,31:1119–1125
20 Selvaraj S R,Dixon J,Bansal V,et al.Whole-genome haplotype reconstruction using proximity-ligation and shotgun sequencing.Nature Biotechnol,2013,31:1111–1118
21 Nagano T,Lubling Y,Stevens T J,et al.Single-cell Hi-C reveals cell-to-cell variability in chromosome structure.Nature,2013,502:59–64
22 Li G,Fullwood M J,Xu H,et al.ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing.Genome Biol,2010,11:R22
23 Yaffe E,Tanay A.Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture.Nat Genet,2011,43:1059–1065
24 Imakaev M,Fudenberg G,McCord R P,et al.Iterative correction of Hi-C data reveals hallmarks of chromosome organization.Nat Methods,2012,9:999–1003
25 Langer-Safer P R,Levine M,Ward D C.Immunological method for mapping genes on Drosophila polytene chromosomes.Proc Natl Acad Sci USA,1982,79:4381–4385
26 Doksani Y,Wu J Y,de Lange T,et al.Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation.Cell,2013,155:345–356
27 Kim Y G,Cha J,Chandrasegaran S.Hybrid restriction enzymes:Zinc finger fusions to Fok I cleavage domain.Proc Natl Acad Sci USA,1996,93:1156–1160
28 Boch J.TALEs of genome targeting.Nat Biotechnol,2011,29:135–136
29 Cong L,Ran F A,Cox D,et al.Multiplex genome engineering using CRISPR/Cas systems.Science,2013,339:819–823
30 Deng W,Lee J,Wang H,et al.Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor.Cell,2012,149:1233–1244
31 Fanucchi S,Shibayama Y,Burd S,et al.Chromosomal contact permits transcription between coregulated genes.Cell,2013,155:606–620
32 Ran F A,Hsu P D,Lin C Y,et al.Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity.Cell,2013,154:1380–1389
33 Hu M,Deng K,Qin Z,et al.Bayesian inference of spatial organizations of chromosomes.PLoS Comput Biol,2013,9:e1002893
34 Zhang Z,Li G,Toh K C,et al.3D chromosome modeling with semi-definite programming and Hi-C data.J Comput Biol,2013,20:831–846
35 Sandhu K S,Li G,Sung W K,et al.Chromatin interaction networks and higher order architectures of eukaryotic genomes.J Cell Biochem,2011,112:2218–2221
36 Sandhu K S,Li G,Poh H M,et al.Large-scale functional organization of long-range chromatin interaction networks.Cell Rep,2012,2:1207–1219
2 The ENCODE Project Consortium.An integrated encyclopedia of DNA elements in the human genome.Nature,2012,489:57–74
3 Cremer T,Cremer C.Chromosome territories,nuclear architecture and gene regulation in mammalian cells.Nat Rev Genet,2001,2:292–301
4 Ruan Y.Genome-sequencing anniversary.Presenting the human genome:Now in 3D!Science,2011,331:1025–1026
5 Fullwood M J,Liu M H,Pan Y F,et al.An oestrogen-receptor-alpha-bound human chromatin interactome.Nature,2009,462:58–64
6 Li G,Ruan X,Auerbach R K,et al.Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation.Cell,2012,148:84–98
7 Cremer T,Cremer M.Chromosome territories.Cold Spring Harbor Perspectives Biol,2010,2:a003889
8 Dekker J,Rippe K,Dekker M,et al.Capturing chromosome conformation.Science,2002,295:1306–1311
9 Simonis M,Klous P,Splinter E,et al.Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip(4C).Nat Genet,2006,38:1348–1354
10 Zhao Z,Tavoosidana G,Sjlinder M,et al.Circular chromosome conformation capture(4C)uncovers extensive networks of epigenetically regulated intra-and interchromosomal interactions.Nat Genet,2006,38:1341–1347
11 Dostie J,Richmond T A,Arnaout R A,et al.Chromosome Conformation Capture Carbon Copy(5C):A massively parallel solution for mapping interactions between genomic elements.Genome Res,2006,16:1299–1309
12 Lieberman-Aiden E,van Berkum N L,Williams L,et al.Comprehensive mapping of long-range interactions reveals folding principles of the human genome.Science,2009,326:289–293
13 Kieffer-Kwon K R,Tang Z,Mathe E,et al.CTCF-mediated functional chromatin interactome in pluripotent cells.Nat Genet,2011,43:630–638
14 Handoko L,Xu H,Li G,et al.Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations.Nature,2013,504:306–310
15 Kieffer-Kwon K R,Tang Z,Mathe E,et al.Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.Cell,2013,155:1507–1520
16 DeMare L E,Leng J,Cotney J,et al.The genomic landscape of cohesin-associated chromatin interactions.Genome Res,2013,23:1224–1234
17 Chepelev I,Wei G,Wangsa D,et al.Characterization of genome-wide enhancer-promoter interactions reveals co-expression of interacting genes and modes of higher order chromatin organization.Cell Res,2012,22:490–503
18 Zhang Y,McCord R P,Ho Y J,et al.Spatial organization of the mouse genome and its role in recurrent chromosomal translocations.Cell,2012,148:908–921
19 Burton J N,Adey A,Patwardhan R P,et al.Chromosome-scale scaffolding of de novo genome assemblies based on chromatin interactions.Nat Biotechnol,2013,31:1119–1125
20 Selvaraj S R,Dixon J,Bansal V,et al.Whole-genome haplotype reconstruction using proximity-ligation and shotgun sequencing.Nature Biotechnol,2013,31:1111–1118
21 Nagano T,Lubling Y,Stevens T J,et al.Single-cell Hi-C reveals cell-to-cell variability in chromosome structure.Nature,2013,502:59–64
22 Li G,Fullwood M J,Xu H,et al.ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing.Genome Biol,2010,11:R22
23 Yaffe E,Tanay A.Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture.Nat Genet,2011,43:1059–1065
24 Imakaev M,Fudenberg G,McCord R P,et al.Iterative correction of Hi-C data reveals hallmarks of chromosome organization.Nat Methods,2012,9:999–1003
25 Langer-Safer P R,Levine M,Ward D C.Immunological method for mapping genes on Drosophila polytene chromosomes.Proc Natl Acad Sci USA,1982,79:4381–4385
26 Doksani Y,Wu J Y,de Lange T,et al.Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation.Cell,2013,155:345–356
27 Kim Y G,Cha J,Chandrasegaran S.Hybrid restriction enzymes:Zinc finger fusions to Fok I cleavage domain.Proc Natl Acad Sci USA,1996,93:1156–1160
28 Boch J.TALEs of genome targeting.Nat Biotechnol,2011,29:135–136
29 Cong L,Ran F A,Cox D,et al.Multiplex genome engineering using CRISPR/Cas systems.Science,2013,339:819–823
30 Deng W,Lee J,Wang H,et al.Controlling long-range genomic interactions at a native locus by targeted tethering of a looping factor.Cell,2012,149:1233–1244
31 Fanucchi S,Shibayama Y,Burd S,et al.Chromosomal contact permits transcription between coregulated genes.Cell,2013,155:606–620
32 Ran F A,Hsu P D,Lin C Y,et al.Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity.Cell,2013,154:1380–1389
33 Hu M,Deng K,Qin Z,et al.Bayesian inference of spatial organizations of chromosomes.PLoS Comput Biol,2013,9:e1002893
34 Zhang Z,Li G,Toh K C,et al.3D chromosome modeling with semi-definite programming and Hi-C data.J Comput Biol,2013,20:831–846
35 Sandhu K S,Li G,Sung W K,et al.Chromatin interaction networks and higher order architectures of eukaryotic genomes.J Cell Biochem,2011,112:2218–2221
36 Sandhu K S,Li G,Poh H M,et al.Large-scale functional organization of long-range chromatin interaction networks.Cell Rep,2012,2:1207–1219