基于Hi-c数据的酵母染色体三维结构重构

通过染色体交互频率数据(Hi-c)来预测染色体三维空间结构是近年表观遗传研究热点。研究表明染色体三维空间结构在生物基因表达、调控等方面起到重要作用,对其进行三维重构是研究细胞代谢过程的基本途径。针对酵母Hi-c数据在不同染色体所呈现出的统计特征,拟合出每条染色体交互频率数据分布的数学模型,然后利用梯度上升迭代算法预测并重构其三维结构,并给出模型评估指标。实验结果表明,模型具有较高可重复性和预测精确度。     

染色质三维结构重建及其生物学意义

真核生物的基因组在细胞核中以染色质的形式存在,染色质的功能与它的三维结构紧密相关,例如,基因组的复制、转录、调控、DNA突变、长链非编码RNA的传播和胚胎发育等生物功能都是在细胞核的三维空间中完成的.随着染色体构象捕获及其衍生技术与高通量测序技术的结合,产生了大量的染色质交互作用数据.根据这些染色质交互作用数据,研究人员已经提出很多种方法来重建染色质的三维结构.这些方法有助于在不同分辨率下系统地研究染色质的三维结构,为更好地了解染色质的调控功能提供了结构依据.本文总结了近期染色质三维结构建模方法的进展,并探讨了其在研究染色质生物学功能方面的应用.     

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正染色体三维结构重构Three-dimensional reconstruction of chromosomes染色体三维重构是近年来基因组学研究的重要手段,利用测序技术获得的染色体空间结构信息,本质是根据染色体二维接触频率数据来预测其在细胞核中的三维形态。基于染色体构象捕获(Chromosome conformation capture,3C)技术的高通量Hi-C(High-throughput/resolution chromosome conformation capture)     

影响染色体三维结构的主要因素及其研究进展

染色体的三维结构与基因表达的精准调控密切相关,染色体空间结构的改变也常会影响细胞中多种生物学活动的有序进行.近年来,染色质空间构象捕获技术和测序技术的发展,使得三维基因组学的研究取得一系列进展.科学家们发现,染色质逐级折叠压缩,具有严密的层级结构,而影响染色质三维结构的因素则涉及DNA序列和蛋白复合体等多个方面.本文综述了影响三维基因组结构的主要因素,包括一维基因组层面上的DNA序列及其共价修饰、与基因结构以及顺式调控元件相互作用的蛋白复合体、核小体排布与组蛋白修饰以及在有丝分裂和染色体多倍化等过程中特有的三维结构变化等多个方面.通过总结这些因素如何影响染色体的三维结构以及相关的研究现状,揭示了染色体三维结构研究的重要作用.本文还简要总结了三维基因组学研究所面临的主要问题,并据此展望该领域将来的主要研究方向和可能的应用前景.     

基因组三维结构研究进展

由于三维基因组结构在基因调控和细胞功能中起到了关键性作用,因此了解染色质是如何在细胞核内组织,以及这种三维结构如何影响基因调控、决定细胞命运和推动物种演变是当前生命科学研究的主要命题之一.本综述首先描述了与基因组三维结构密切相关的主要染色质构象捕获技术,然后介绍了常用的基因组三维结构重构算法和相关可视化工具,最后结合应用阐述三维基因组研究目前存在的问题和未来的发展方向.     

利用改进的3DMax算法重构染色体3D结构

近年来,随着高通量染色体构象捕获(Hi-C)等技术的发展和高通量测序成本的降低,全基因组交互作用的数据量快速增长,交互作用图谱分辨率不断提高,促使染色体和基因组三维结构建模的研究取得了很大进展,已经提出了几种从染色体构象捕捉数据中构建单个染色体或整个基因组结构的方法。文中通过对在 Hi-C 数据基础上对染色体三维结构重建的相关文献进行分析,总结了重建染色体三维空间结构的经典算法3DMax的原理,并且提出了一种新的随机梯度上升算法:XNadam,是Nadam优化方法的一个变体,将其应用于3DMax算法中,以便提高3DMax算法的性能,从而用于预测染色体三维结构。     

综述: 冷冻电镜技术在表观遗传学研究中的应用

染色质装配、修饰和重塑复合体,以及它们和核小体、染色质等一起形成的超大分子复合体的精细结构解析,对于在原子水平揭示表观遗传信息建立、维持和调控的分子机制至关重要．近年来,迅速发展的冷冻电镜三维重构技术对于解析这些多亚基、大分子质量、柔性超大分子复合体的结构带来了很好的机遇．本文综述了冷冻电镜三维重构技术在表观遗传学相关的结构研究领域中的一些应用和进展．     

冷冻电镜技术在表观遗传学研究中的应用

染色质装配、修饰和重塑复合体,以及它们和核小体、染色质等一起形成的超大分子复合体的精细结构解析,对于在原子水平揭示表观遗传信息建立、维持和调控的分子机制至关重要.近年来,迅速发展的冷冻电镜三维重构技术对于解析这些多亚基、大分子质量、柔性超大分子复合体的结构带来了很好的机遇.本文综述了冷冻电镜三维重构技术在表观遗传学相关的结构研究领域中的一些应用和进展.     

浅谈染色质高级结构与基因转录的远程调控

精确的基因表达调控是细胞分化、个体发育和细胞维持正常生命活动的必要条件,转录调控是真核细胞基因表达调控最关键的环节,其神秘和精深吸引着无数科学家为之奋斗不已。染色质构象捕获及其衍生技术的建立和2003年启动的"DNA元件百科全书"计划,将人们对基因转录调控的认识从二维层面推向三维空间。基因组中分布着众多调控元件,它们与所调控的靶基因间可相距几万甚至几十万个核苷酸,可以与靶基因位于相同或不同的染色体上。依据染色质环模型,调控元件可通过染色质环高级结构,与靶基因在空间上充分接近并相互作用,发挥其调控功能。同一个调控元件可以调控不同的靶基因,而相同的基因亦可能受不同调控元件的调节,由此细胞在染色质高级结构层面形成了一个复杂的调节基因转录活性的三维网络。该文分别从基因远程调控现象的发现、研究方法、相关机制及面临的挑战等方面作一简要综述。     

树鼩脑三维结构重建的研究 Ⅲ.脑外形立体结构的计算机辅助绘图

作者曾经详细介绍过树鼩脑切片二维结构重建的数据采集、计算机处理数据的算法及图形生成技术。在此基础上,本文介绍树鼩脑三维结构重建的数学模型及其自动生成三维图形的基本技术与计算机绘图的部分结果。     

Three-dimensional light microscopy of diploid Drosophila chromosomes

Fluorescence microscopy, uniquely, provides the ability to examine specific components within intact, even living, cells. Unfortunately, high-resolution conventional fluorescence microscopy is intrinsically a two-dimensional technique and performs poorly with specimens thicker than about 0.5 micron. Probing the spatial organization of components within cells has required the development of new methods optimized for three-dimensional data collection, processing, display, and interpretation. Our interest in understanding the relationship between chromosome structure and function has led us to develop the necessary methodology for exploring cell structures in three dimensions. It is now possible to determine directly the three-dimensional spatial organization of diploid chromosomes within intact nuclei throughout most of the mitotic the cell cycle.     

基于生物信息学的Hi-C研究现状与发展趋势

染色体的空间交互作用被视为影响基因表达调控的重要因素,高通量染色体构象捕获(high-throughput chromosome conformation capture,Hi-C)技术已成为3D基因组学中探索染色体空间交互作用的主要实验手段之一。随着Hi-C样本数据的持续累积以及分析处理流程复杂度的不断提升,基于生物信息学的Hi-C数据分析对探究基因表达的时空调控机制而言,是机遇也是挑战。本文从生物信息学角度,综合阐述了Hi-C的国内外研究现状及发展动态,包括数据标准化、多级结构分析、数据可视化以及三维建模,重点剖析了多级结构中的A/B区室(A/B compartments)、拓扑相关域(topological associated domains,TADs)和染色质环(chromain looping),在此基础上分析了该方向未来可能的研究热点及发展趋势,以期为将基因表达调控的探索从传统线性空间进一步拓展到三维结构空间提供支持。     

Tissue-specific spatial organization of genomes

Background

Genomes are organized in vivo in the form of chromosomes. Each chromosome occupies a distinct nuclear subvolume in the form of a chromosome territory. The spatial positioning of chromosomes within the interphase nucleus is often nonrandom. It is unclear whether the nonrandom spatial arrangement of chromosomes is conserved among tissues or whether spatial genome organization is tissue-specific.

Results

Using two-dimensional and three-dimensional fluorescence in situ hybridization we have carried out a systematic analysis of the spatial positioning of a subset of mouse chromosomes in several tissues. We show that chromosomes exhibit tissue-specific organization. Chromosomes are distributed tissue-specifically with respect to their position relative to the center of the nucleus and also relative to each other. Subsets of chromosomes form distinct types of spatial clusters in different tissues and the relative distance between chromosome pairs varies among tissues. Consistent with the notion that nonrandom spatial proximity is functionally relevant in determining the outcome of chromosome translocation events, we find a correlation between tissue-specific spatial proximity and tissue-specific translocation prevalence.

Conclusions

Our results demonstrate that the spatial organization of genomes is tissue-specific and point to a role for tissue-specific spatial genome organization in the formation of recurrent chromosome arrangements among tissues.

     

Three-dimensional organization of Drosophila melanogaster interphase nuclei. I. Tissue-specific aspects of polytene nuclear architecture

Interphase chromosome organization in four different Drosophila melanogaster tissues, covering three to four levels of polyteny, has been analyzed. The results are based primarily on three-dimensional reconstructions from unfixed tissues using a computer-based data collection and modeling system. A characteristic organization of chromosomes in each cell type is observed, independent of polyteny, with some packing motifs common to several or all tissues and others tissue-specific. All chromosomes display a right-handed coiling chirality, despite large differences in size and degree of coiling. Conversely, in each cell type, the heterochromatic centromeric regions have a unique structure, tendency to associate, and intranuclear location. The organization of condensed nucleolar chromatin is also tissue-specific. The tightly coiled prothoracic gland chromosomes are arrayed in a similar fashion to the much larger salivary gland chromosomes described previously, having polarized orientations, nonintertwined spatial domains, and close packing of the arms of each autosome, whereas hindgut and especially the unusually straight midgut chromosomes display striking departures from these regularities. Surprisingly, gut chromosomes often appear to be broken in the centric heterochromatin. Severe deformations of midgut nuclei observed during gut contractions in living larvae may account for their unusual properties. Finally, morphometric measurements of chromosome and nuclear dimensions provide insights into chromosome growth and substructure and also suggest an unexpected parallel with diploid chromatin organization.     

Well-defined genome architecture in the human sperm nucleus

Using fluorescence in situ hybridization, conventional epifluorescence microscopy, and laser scanning confocal microscopy followed by three-dimensional reconstruction we describe a well-defined higher order packaging of the human genome in the sperm cell nucleus. This was determined by the spatial localization of centromere and telomere regions of all chromosomes and supported by localization of subtelomere sequences of chromosome 3 and the entire chromosome 2. The nuclear architecture in the human sperm is characterized by the clustering of the 23 centromeres into a compact chromocenter positioned well inside the nucleus. The ends of the chromosomes are exposed to the nuclear periphery where both the subtelomere and the telomere sequences of the chromosome arms are joined into dimers. Thus chromosomes in the human sperm nucleus are looped into a hairpin-like configuration. The biological implications of this nuclear architecture in spermatogenesis and male pronuclear formation following fertilization are discussed.     

Evolutionary significance of chromosome architecture for epigenetic control of eukaryote development and phylogeny

The significance of the spatial organization of chromosomes in germline tissue as a positional system controlling segregation in oogenesis is considered. The history of the problem is reviewed. The author's data on reorganization of chromosome structure in germline tissue considered in terms of systemic mutations are systematized. The notion of specific morphogenetic field based on chromosome structure, which controls ooplasmic segregation and subsequent developmental stages, is developed.     

Evolutionary significance of chromosome architecture for epigenetic control of eukaryote development and phylogeny

The significance of the spatial organization of chromosomes in germline tissue as a positional system controlling segregation in oogenesis is considered. The history of the problem is reviewed. The author’s data on reorganization of chromosome structure in germline tissue considered in terms of systemic mutations are systematized. The notion of specific morphogenetic field based on chromosome structure, which controls ooplasmic segregation and subsequent developmental stages, is developed.