Comprehensive mapping of long-range interactions reveals folding principles of the human genome.
09 Oct 2009-Science (American Association for the Advancement of Science)-Vol. 326, Iss: 5950, pp 289-293
TL;DR: Hi-C is described, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing and demonstrates the power of Hi-C to map the dynamic conformations of entire genomes.
Abstract: We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.
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TL;DR: The reference genome of the Vernal Pool Fairy Shrimp Branchinecta lynchi is presented to better understand the adaptive capacity of this imperiled species, as well as answer lingering questions about anostracan physiology, sex determination and development.
Abstract: Abstract We present the reference genome of the Vernal Pool Fairy Shrimp Branchinecta lynchi. This branchiopod crustacean is endemic to California’s freshwater ephemeral ponds. It faces enormous habitat loss and fragmentation as urbanization and agriculture have fundamentally changed the vernal pool landscape over the past 3 centuries. The assembled genome consists of 22 chromosome-length scaffolds that account for 96.85% of the total sequence. One hundred and ninety-five unscaffolded contigs comprise the rest of the genome’s 575.6 Mb length. The genome is substantially complete with a BUSCO score of 90.0%. There is no immediately identifiable sex chromosome, typical for this class of organism. This new resource will permit researchers to better understand the adaptive capacity of this imperiled species, as well as answer lingering questions about anostracan physiology, sex determination, and development.
1 citations
TL;DR: In this paper , the authors consider a model where a dense cycle with expected bandwidth $n \tau$ and edge density $p$ is planted in an Erd\H{o}s-R\'enyi graph and characterize the computational thresholds for the associated detection and recovery problems for the class of low degree polynomial algorithms.
Abstract: Planted dense cycles are a type of latent structure that appears in many applications, such as small-world networks in social sciences and sequence assembly in computational biology. We consider a model where a dense cycle with expected bandwidth $n \tau$ and edge density $p$ is planted in an Erd\H{o}s-R\'enyi graph $G(n,q)$. We characterize the computational thresholds for the associated detection and recovery problems for the class of low-degree polynomial algorithms. In particular, a gap exists between the two thresholds in a certain regime of parameters. For example, if $n^{-3/4} \ll \tau \ll n^{-1/2}$ and $p = C q = \Theta(1)$ for a constant $C>1$, the detection problem is computationally easy while the recovery problem is hard for low-degree algorithms.
1 citations
TL;DR: In this paper , the authors show that simple translocations and complex rearrangements are formed through illegitimate ligations of double-strand breaks of fusion partners and lead to generation of oncogenic fusion genes that affect cellular function.
Abstract: Simple translocations and complex rearrangements are formed through illegitimate ligations of double-strand breaks of fusion partners and lead to generation of oncogenic fusion genes that affect cellular function. The contact first hypothesis states that fusion partners tend to colocalize prior to fusion in normal cells. Here we test this hypothesis at the single-cell level and explore the underlying mechanism.By analyzing published single-cell diploid Hi-C datasets, we find partner genes fused in leukemia exhibit smaller spatial distances than those fused in solid tumor and control gene pairs. Intriguingly, multiple partners tend to colocalize with KMT2A in the same cell. 3D genome architecture has little association with lineage decision of KMT2A fusion types in leukemia. Besides simple translocations, complex rearrangement-related KMT2A fusion genes (CRGs) also show closer proximity and belong to a genome-wide mutual proximity network. We find CRGs are co-expressed, co-localized, and enriched in the targets of the transcriptional factor RUNX1, suggesting they may be involved in RUNX1-mediated transcription factories. Knockdown of RUNX1 leads to significantly fewer contacts among CRGs. We also find CRGs are enriched in active transcriptional regions and loop anchors, and exhibit high levels of TOP2-mediated DNA breakages. Inhibition of transcription leads to reduced DNA breakages of CRGs.Our results demonstrate KMT2A partners and CRGs may form dynamic and multipartite spatial clusters in individual cells that may be involved in RUNX1-mediated transcription factories, wherein massive DNA damages and illegitimate ligations of genes may occur, leading to complex rearrangements and KMT2A fusions in leukemia.
1 citations
DOI•
01 Jan 2015
TL;DR: This work discovers and characterize activities that the ATP-dependent chromatin remodeling enzyme SWI/SNF uses to disrupt repressive heterochromatin structure, and finds that this Sir3p eviction activity is required for proper DNA replication, and for establishment of silent chromatin.
Abstract: Eukaryotic DNA is incorporated into the nucleoprotein structure of chromatin. This structure is essential for the proper storage, maintenance, regulation, and function of the genomes’ constituent genes and genomic sequences. Importantly, cells generate discrete types of chromatin that impart distinct properties on genomic loci; euchromatin is an open and active compartment of the genome, and heterochromatin is a restricted and inactive compartment. Heterochromatin serves many purposes in vivo, from heritably silencing key gene loci during embryonic development, to preventing aberrant DNA repeat recombination. Despite this generally repressive role, the DNA contained within heterochromatin must still be repaired and replicated, creating a need for regulated dynamic access into silent heterochromatin. In this work, we discover and characterize activities that the ATP-dependent chromatin remodeling enzyme SWI/SNF uses to disrupt repressive heterochromatin structure. First, we find two specific physical interactions between the SWI/SNF core subunit Swi2p and the heterochromatin structural protein Sir3p. We find that disrupting these physical interactions results in a SWI/SNF complex that can hydrolyze ATP and slide nucleosomes like normal, but is defective in its ability to evict Sir3p off of heterochromatin. In vivo, we find that this Sir3p eviction activity is required for proper DNA replication, and for establishment of silent chromatin,
1 citations
Cites background from "Comprehensive mapping of long-range..."
...…chromosome conformation capture methodology, which crosslinks spatially close genomic loci together to derive information about overall genome packaging, imply the existence of large-scale topologically associated domains (TADs) in metazoan cells (Lieberman-Aiden et al., 2009; Dixon et al., 2012)....
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...While these types of chromatin are constrained in a linear sense to contiguous domains by boundary factors like CTCF, two chromatin domains that share common features and proteins are more likely to share spatial proximity with one another than two dissimilar but linearly adjacent loci are (Lieberman-Aiden et al., 2009; Rao et al., 2014)....
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...topologically associated domains (TADs) in metazoan cells (Lieberman-Aiden et al., 2009; Dixon et al., 2012)....
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...Interestingly, these domains interact with other domains in ways that correlate with the organization of genomes into active and repressed regions, or euchromatin vs. heterochromatin (Lieberman-Aiden et al., 2009; Rao et al., 2014)....
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TL;DR: Super-resolution microscopy (SRM) is a prime tool to study chromatin organization at near biomolecular resolution in the native cellular environment as discussed by the authors , with fluorescent labels DNA, chromatin-associated proteins and specific epigenetic states can be identified with high molecular specificity.
Abstract: Abstract Super-resolution microscopy (SRM) is a prime tool to study chromatin organisation at near biomolecular resolution in the native cellular environment. With fluorescent labels DNA, chromatin-associated proteins and specific epigenetic states can be identified with high molecular specificity. The aim of this review is to introduce the field of diffraction-unlimited SRM to enable an informed selection of the most suitable SRM method for a specific chromatin-related research question. We will explain both diffraction-unlimited approaches (coordinate-targeted and stochastic-localisation-based) and list their characteristic spatio-temporal resolutions, live-cell compatibility, image-processing, and ability for multi-colour imaging. As the increase in resolution, compared to, e.g. confocal microscopy, leads to a central role of the sample quality, important considerations for sample preparation and concrete examples of labelling strategies applicable to chromatin research are discussed. To illustrate how SRM-based methods can significantly improve our understanding of chromatin functioning, and to serve as an inspiring starting point for future work, we conclude with examples of recent applications of SRM in chromatin research.
1 citations
References
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TL;DR: This book is a blend of erudition, popularization, and exposition, and the illustrations include many superb examples of computer graphics that are works of art in their own right.
Abstract: "...a blend of erudition (fascinating and sometimes obscure historical minutiae abound), popularization (mathematical rigor is relegated to appendices) and exposition (the reader need have little knowledge of the fields involved) ...and the illustrations include many superb examples of computer graphics that are works of art in their own right." Nature
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"Comprehensive mapping of long-range..." refers background in this paper
...The resulting structure resembles a Peano curve, a continuous fractal trajectory that densely fills three-dimensional space without crossing itself (29)....
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TL;DR: PfPMP1）与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。
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"Comprehensive mapping of long-range..." refers background in this paper
...Power-law dependencies can arise from polymer-like behavior (24)....
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TL;DR: The application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells is reported and it is shown that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms.
Abstract: We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences Lysine 4 and lysine 9 trimethylation marks imprinting control regions Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations
4,166 citations
TL;DR: Using the yeast Saccharomyces cerevisiae, this work could confirm known qualitative features of chromosome organization within the nucleus and dynamic changes in that organization during meiosis and found that chromatin is highly flexible throughout.
Abstract: We describe an approach to detect the frequency of interaction between any two genomic loci. Generation of a matrix of interaction frequencies between sites on the same or different chromosomes reveals their relative spatial disposition and provides information about the physical properties of the chromatin fiber. This methodology can be applied to the spatial organization of entire genomes in organisms from bacteria to human. Using the yeast Saccharomyces cerevisiae, we could confirm known qualitative features of chromosome organization within the nucleus and dynamic changes in that organization during meiosis. We also analyzed yeast chromosome III at the G1 stage of the cell cycle. We found that chromatin is highly flexible throughout. Furthermore, functionally distinct AT- and GC-rich domains were found to exhibit different conformations, and a population-average 3D model of chromosome III could be determined. Chromosome III emerges as a contorted ring.
3,465 citations