Comparing 3D genome organization in multiple species using Phylo-HMRF

AbstractRecent developments in whole-genome mapping approaches for the chromatin interactome (such as Hi-C) have offered new insights into 3D genome organization. However, our knowledge of the evolutionary patterns of 3D genome structures in mammalian species remains surprisingly limited. In particular, there are no existing phylogenetic-model based methods to analyze chromatin interactions as continuous features across different species. Here we develop a new probabilistic model, named phylogenetic hidden Markov random field (Phylo-HMRF), to identify evolutionary patterns of 3D genome structures based on multi-species Hi-C data by jointly utilizing spatial constraints among genomic loci and continuous-trait evolutionary models. The effectiveness of Phylo-HMRF is demonstrated in both simulation evaluation and application to real Hi-C data. We used Phylo-HMRF to uncover cross-species 3D genome patterns based on Hi-C data from the same cell type in four primate species (human, chimpanzee, bonobo, and gorilla). The identified evolutionary patterns of 3D genome organization correlate with features of genome structure and function, including long-range interactions, topologically-associating domains (TADs), and replication timing patterns. This work provides a new framework that utilizes general types of spatial constraints to identify evolutionary patterns of continuous genomic features and has the potential to reveal the evolutionary principles of 3D genome organization.

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Impact of DNA methylation on 3D genome structure

Nature Communications ◽

10.1038/s41467-021-23142-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Diana Buitrago ◽

Mireia Labrador ◽

Juan Pablo Arcon ◽

Rafael Lema ◽

Oscar Flores ◽

...

Keyword(s):

Dna Methylation ◽

Chromatin Structure ◽

Chromatin Condensation ◽

Genome Structure ◽

Dna Methyltransferases ◽

Model System ◽

Structure And Function ◽

3D Genome ◽

Cellular Machinery ◽

And Function

AbstractDetermining the effect of DNA methylation on chromatin structure and function in higher organisms is challenging due to the extreme complexity of epigenetic regulation. We studied a simpler model system, budding yeast, that lacks DNA methylation machinery making it a perfect model system to study the intrinsic role of DNA methylation in chromatin structure and function. We expressed the murine DNA methyltransferases in Saccharomyces cerevisiae and analyzed the correlation between DNA methylation, nucleosome positioning, gene expression and 3D genome organization. Despite lacking the machinery for positioning and reading methylation marks, induced DNA methylation follows a conserved pattern with low methylation levels at the 5’ end of the gene increasing gradually toward the 3’ end, with concentration of methylated DNA in linkers and nucleosome free regions, and with actively expressed genes showing low and high levels of methylation at transcription start and terminating sites respectively, mimicking the patterns seen in mammals. We also see that DNA methylation increases chromatin condensation in peri-centromeric regions, decreases overall DNA flexibility, and favors the heterochromatin state. Taken together, these results demonstrate that methylation intrinsically modulates chromatin structure and function even in the absence of cellular machinery evolved to recognize and process the methylation signal.

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Replication Timing Becomes Intertwined with 3D Genome Organization

Cell ◽

10.1016/j.cell.2019.01.027 ◽

2019 ◽

Vol 176 (4) ◽

pp. 681-684 ◽

Cited By ~ 2

Author(s):

Jian Ma ◽

Zhijun Duan

Keyword(s):

Genome Organization ◽

Replication Timing ◽

3D Genome

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The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions

10.1101/112268 ◽

2017 ◽

Cited By ~ 34

Author(s):

Yanli Wang ◽

Bo Zhang ◽

Lijun Zhang ◽

Lin An ◽

Jie Xu ◽

...

Keyword(s):

Genome Organization ◽

Target Genes ◽

Genome Structure ◽

Regulatory Elements ◽

Genomic Region ◽

Genome Browser ◽

Chromatin Interaction ◽

Interaction Data ◽

3D Genome ◽

Chromatin Interactions

ABSTRACTRecent advent of 3C-based technologies such as Hi-C and ChIA-PET provides us an opportunity to explore chromatin interactions and 3D genome organization in an unprecedented scale and resolution. However, it remains a challenge to visualize chromatin interaction data due to its size and complexity. Here, we introduce the 3D Genome Browser (http://3dgenome.org), which allows users to conveniently explore both publicly available and their own chromatin interaction data. Users can also seamlessly integrate other “omics” data sets, such as ChIP-Seq and RNA-Seq for the same genomic region, to gain a complete view of both regulatory landscape and 3D genome structure for any given gene. Finally, our browser provides multiple methods to link distal cis-regulatory elements with their potential target genes, including virtual 4C, ChIA-PET, Capture Hi-C and cross-cell-type correlation of proximal and distal DNA hypersensitive sites, and therefore represents a valuable resource for the study of gene regulation in mammalian genomes.

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Cohesin-Mediated Genome Architecture Does Not Define DNA Replication Timing Domains

Genes ◽

10.3390/genes10030196 ◽

2019 ◽

Vol 10 (3) ◽

pp. 196 ◽

Cited By ~ 6

Author(s):

Phoebe Oldach ◽

Conrad A. Nieduszynski

Keyword(s):

Dna Replication ◽

Genome Organization ◽

Mammalian Cells ◽

Replication Timing ◽

S Phase ◽

Genome Architecture ◽

3D Genome ◽

Synchronized Cells ◽

Dna Replication Timing ◽

Phase Entry

3D genome organization is strongly predictive of DNA replication timing in mammalian cells. This work tested the extent to which loop-based genome architecture acts as a regulatory unit of replication timing by using an auxin-inducible system for acute cohesin ablation. Cohesin ablation in a population of cells in asynchronous culture was shown not to disrupt patterns of replication timing as assayed by replication sequencing (RepliSeq) or BrdU-focus microscopy. Furthermore, cohesin ablation prior to S phase entry in synchronized cells was similarly shown to not impact replication timing patterns. These results suggest that cohesin-mediated genome architecture is not required for the execution of replication timing patterns in S phase, nor for the establishment of replication timing domains in G1.

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Targeted mutations on 3D hub loci alter spatial interaction environment

10.1101/030999 ◽

2015 ◽

Author(s):

Bo Ding ◽

Lina Zheng ◽

David Medovoy ◽

Wei Wang

Keyword(s):

Genome Organization ◽

Spatial Organization ◽

Spatial Interaction ◽

Genome Structure ◽

Chromosomal Structure ◽

Scale Free ◽

3D Genome ◽

Coding Regions ◽

Gene Coding ◽

Related Genotype

Many disease-related genotype variations (GVs) reside in non-gene coding regions and the mechanisms of their association with diseases are largely unknown. A possible impact of GVs on disease formation is to alter the spatial organization of chromosome. However, the relationship between GVs and 3D genome structure has not been studied at the chromosome scale. The kilobase resolution of chromosomal structures measured by Hi-C have provided an unprecedented opportunity to tackle this problem. Here we proposed a network-based method to capture global properties of the chromosomal structure. We uncovered that genome organization is scale free and the genomic loci interacting with many other loci in space, termed as hubs, are critical for stabilizing local chromosomal structure. Importantly, we found that cancer-specific GVs target hubs to drastically alter the local chromosomal interactions. These analyses revealed the general principles of 3D genome organization and provided a new direction to pinpoint genotype variations in non-coding regions that are critical for disease formation.

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Easy Hi-C: A simple efficient protocol for 3D genome mapping in small cell populations

10.1101/245688 ◽

2018 ◽

Cited By ~ 6

Author(s):

Leina Lu ◽

Xiaoxiao Liu ◽

Jun Peng ◽

Yan Li ◽

Fulai Jin

Keyword(s):

Genome Organization ◽

Genome Mapping ◽

Mammalian Genome ◽

Small Cell ◽

Genome Architecture ◽

Enzymatic Reactions ◽

High Quality ◽

3D Genome ◽

Proximity Ligation ◽

Genome Wide

Despite the growing interest in studying the mammalian genome organization, it is still challenging to map the DNA contacts genome-wide. Here we present easy Hi-C (eHi-C), a highly efficient method for unbiased mapping of 3D genome architecture. The eHi-C protocol only involves a series of enzymatic reactions and maximizes the recovery of DNA products from proximity ligation. We show that eHi-C can be performed with 0.1 million cells and yields high quality libraries comparable to Hi-C.

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Probing multi-way chromatin interaction with hypergraph representation learning

10.1101/2020.01.22.916171 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ruochi Zhang ◽

Jian Ma

Keyword(s):

Genome Organization ◽

Representation Learning ◽

Higher Order ◽

Computational Method ◽

Chromatin Interaction ◽

Interaction Data ◽

3D Genome ◽

Chromatin Interactions ◽

Single Nucleus ◽

And Function

AbstractAdvances in high-throughput mapping of 3D genome organization have enabled genome-wide characterization of chromatin interactions. However, proximity ligation based mapping approaches for pairwise chromatin interaction such as Hi-C cannot capture multi-way interactions, which are informative to delineate higher-order genome organization and gene regulation mechanisms at single-nucleus resolution. The very recent development of ligation-free chromatin interaction mapping methods such as SPRITE and ChIA-Drop has offered new opportunities to uncover simultaneous interactions involving multiple genomic loci within the same nuclei. Unfortunately, methods for analyzing multi-way chromatin interaction data are significantly underexplored. Here we develop a new computational method, called MATCHA, based on hypergraph representation learning where multi-way chromatin interactions are represented as hyperedges. Applications to SPRITE and ChIA-Drop data suggest that MATCHA is effective to denoise the data and make de novo predictions of multi-way chromatin interactions, reducing the potential false positives and false negatives from the original data. We also show that MATCHA is able to distinguish between multi-way interaction in a single nucleus and combination of pairwise interactions in a cell population. In addition, the embeddings from MATCHA reflect 3D genome spatial localization and function. MATCHA provides a promising framework to significantly improve the analysis of multi-way chromatin interaction data and has the potential to offer unique insights into higher-order chromosome organization and function.

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DNA methylation is required to maintain both DNA replication timing precision and 3D genome organization integrity

Cell Reports ◽

10.1016/j.celrep.2021.109722 ◽

2021 ◽

Vol 36 (12) ◽

pp. 109722

Author(s):

Qian Du ◽

Grady C. Smith ◽

Phuc Loi Luu ◽

James M. Ferguson ◽

Nicola J. Armstrong ◽

...

Keyword(s):

Dna Methylation ◽

Dna Replication ◽

Genome Organization ◽

Replication Timing ◽

3D Genome ◽

Timing Precision ◽

Dna Replication Timing

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A Drosophila Insulator Interacting Protein Suppresses Enhancer-Blocking Function and Modulates Replication Timing

10.1101/661041 ◽

2019 ◽

Author(s):

Emily C. Stow ◽

Ran An ◽

Todd A. Schoborg ◽

Nastasya M. Davenport ◽

James R. Simmons ◽

...

Keyword(s):

Genome Structure ◽

Nuclear Lamina ◽

Replication Timing ◽

Interacting Protein ◽

Insulator Protein ◽

Protein Partners ◽

Insulator Proteins ◽

Enhancer Blocking ◽

And Function ◽

Partner Proteins

AbstractInsulators play important roles in genome structure and function in Drosophila and mammals. More than six different insulator proteins are required in Drosophila for normal genome function, whereas CTCF is the only identified protein contributing to insulator function in mammals. Interactions between a DNA binding insulator protein and its interacting partner proteins define the properties of each insulator site. The different roles of insulator protein partners in the Drosophila genome and how they confer functional specificity remain poorly understood. Functional analysis of insulator partner proteins in Drosophila is necessary to understand how genomes are compartmentalized and the roles that different insulators play in genome function. In Drosophila, the Suppressor of Hairy wing [Su(Hw)] insulator is targeted to the nuclear lamina, preferentially localizes at euchromatin/heterochromatin boundaries, and is associated with the Gypsy retrotransposon. The properties that the insulator confers to these sites rely on the ability of the Su(Hw) protein to bind the DNA at specific sites and interact with Mod(mdg4)-67.2 and CP190 partner proteins. HP1 and insulator partner protein 1 (HIPP1) is a recently identified partner of Su(Hw), but how HIPP1 contributes to the function of Su(Hw) insulators has not yet been elucidated. Here, we find that mutations in the HIPP1 crotonase-like domain have no impact on the function of Su(Hw) enhancer-blocking activity but do exhibit an impaired ability to repair double-strand breaks. Additionally, we find that the overexpression of each HIPP1 and Su(Hw) causes defects in cell proliferation by limiting the progression of DNA replication. We also find that HIPP1 overexpression suppresses the Su(Hw) insulator enhancer-blocking function.

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Population-based 3D genome structure analysis reveals driving forces in spatial genome organization

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1512577113 ◽

2016 ◽

Vol 113 (12) ◽

pp. E1663-E1672 ◽

Cited By ~ 110

Author(s):

Harianto Tjong ◽

Wenyuan Li ◽

Reza Kalhor ◽

Chao Dai ◽

Shengli Hao ◽

...

Keyword(s):

Genome Organization ◽

Driving Forces ◽

Genome Structure ◽

Probabilistic Approach ◽

Population Based ◽

3D Genome ◽

Structural Variability ◽

Chromatin Interactions ◽

A Genome ◽

Spatial Genome Organization

Conformation capture technologies (e.g., Hi-C) chart physical interactions between chromatin regions on a genome-wide scale. However, the structural variability of the genome between cells poses a great challenge to interpreting ensemble-averaged Hi-C data, particularly for long-range and interchromosomal interactions. Here, we present a probabilistic approach for deconvoluting Hi-C data into a model population of distinct diploid 3D genome structures, which facilitates the detection of chromatin interactions likely to co-occur in individual cells. Our approach incorporates the stochastic nature of chromosome conformations and allows a detailed analysis of alternative chromatin structure states. For example, we predict and experimentally confirm the presence of large centromere clusters with distinct chromosome compositions varying between individual cells. The stability of these clusters varies greatly with their chromosome identities. We show that these chromosome-specific clusters can play a key role in the overall chromosome positioning in the nucleus and stabilizing specific chromatin interactions. By explicitly considering genome structural variability, our population-based method provides an important tool for revealing novel insights into the key factors shaping the spatial genome organization.

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