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Evolutionary stability of topologically associating domains is associated with conserved gene regulation.

ABSTRACT: BACKGROUND:The human genome is highly organized in the three-dimensional nucleus. Chromosomes fold locally into topologically associating domains (TADs) defined by increased intra-domain chromatin contacts. TADs contribute to gene regulation by restricting chromatin interactions of regulatory sequences, such as enhancers, with their target genes. Disruption of TADs can result in altered gene expression and is associated to genetic diseases and cancers. However, it is not clear to which extent TAD regions are conserved in evolution and whether disruption of TADs by evolutionary rearrangements can alter gene expression. RESULTS:Here, we hypothesize that TADs represent essential functional units of genomes, which are stable against rearrangements during evolution. We investigate this using whole-genome alignments to identify evolutionary rearrangement breakpoints of different vertebrate species. Rearrangement breakpoints are strongly enriched at TAD boundaries and depleted within TADs across species. Furthermore, using gene expression data across many tissues in mouse and human, we show that genes within TADs have more conserved expression patterns. Disruption of TADs by evolutionary rearrangements is associated with changes in gene expression profiles, consistent with a functional role of TADs in gene expression regulation. CONCLUSIONS:Together, these results indicate that TADs are conserved building blocks of genomes with regulatory functions that are often reshuffled as a whole instead of being disrupted by rearrangements.

SUBMITTER: Krefting J

PROVIDER: S-EPMC6091198 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Evolutionary stability of topologically associating domains is associated with conserved gene regulation.

Krefting Jan J Andrade-Navarro Miguel A MA Ibn-Salem Jonas J

BMC biology 20180807 1

<h4>Background</h4>The human genome is highly organized in the three-dimensional nucleus. Chromosomes fold locally into topologically associating domains (TADs) defined by increased intra-domain chromatin contacts. TADs contribute to gene regulation by restricting chromatin interactions of regulatory sequences, such as enhancers, with their target genes. Disruption of TADs can result in altered gene expression and is associated to genetic diseases and cancers. However, it is not clear to which e ...[more]

PMID: 30086749

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Project description:Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.

Project description:Chromatin is a polymer complex of DNA and proteins that regulates gene expression. The three-dimensional (3D) structure and organization of chromatin controls DNA transcription and replication. High-throughput chromatin conformation capture techniques generate Hi-C maps that can provide insight into the 3D structure of chromatin. Hi-C maps can be represented as a symmetric matrix [Formula: see text], where each element represents the average contact probability or number of contacts between chromatin loci i and j. Previous studies have detected topologically associating domains (TADs), or self-interacting regions in [Formula: see text] within which the contact probability is greater than that outside the region. Many algorithms have been developed to identify TADs within Hi-C maps. However, most TAD identification algorithms are unable to identify nested or overlapping TADs and for a given Hi-C map there is significant variation in the location and number of TADs identified by different methods. We develop a novel method to identify TADs, KerTAD, using a kernel-based technique from computer vision and image processing that is able to accurately identify nested and overlapping TADs. We benchmark this method against state-of-the-art TAD identification methods on both synthetic and experimental data sets. We find that the new method consistently has higher true positive rates (TPR) and lower false discovery rates (FDR) than all tested methods for both synthetic and manually annotated experimental Hi-C maps. The TPR for KerTAD is also largely insensitive to increasing noise and sparsity, in contrast to the other methods. We also find that KerTAD is consistent in the number and size of TADs identified across replicate experimental Hi-C maps for several organisms. Thus, KerTAD will improve automated TAD identification and enable researchers to better correlate changes in TADs to biological phenomena, such as enhancer-promoter interactions and disease states.

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Evolutionary stability of topologically associating domains is associated with conserved gene regulation.

Publications

Evolutionary stability of topologically associating domains is associated with conserved gene regulation.

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