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Over the past two decades, scientists have increasingly realized the importance of the three-dimensional (3D) genome organization in regulating cellular activity. Hi-C and related experiments yield 2D contact matrices that can be used to infer 3D models of chromosome structure. Visualizing and analyzing genomes in 3D space remains challenging. Here, we present ARGV , an augmented reality 3D Genome Viewer. ARGV contains more than 350 pre-computed and annotated genome structures inferred from Hi-C and imaging data. It offers interactive and collaborative visualization of genomes in 3D space, using standard mobile phones or tablets. A user study comparing ARGV to existing tools demonstrates its benefits.

Centromeres of Candida albicans form on unique and different DNA sequences but a closely related species, Candida tropicalis, possesses homogenized inverted repeat (HIR)-associated centromeres. To investigate the mechanism of centromere type transition, we improved the fragmented genome assembly and constructed a chromosome-level genome assembly of C. tropicalis by employing PacBio sequencing, chromosome conformation capture sequencing (3C-seq), chromoblot, and genetic analysis of engineered aneuploid strains. Further, we analyzed the 3D genome organization using 3C-seq data, which revealed spatial proximity among the centromeres as well as telomeres of seven chromosomes in C. tropicalis. Intriguingly, we observed evidence of inter-centromeric translocations in the common ancestor of C. albicans and C. tropicalis. Identification of putative centromeres in closely related Candida sojae, Candida viswanathii and Candida parapsilosis indicates loss of ancestral HIR-associated centromeres and establishment of evolutionary new centromeres (ENCs) in C. albicans. We propose that spatial proximity of the homologous centromere DNA sequences facilitated karyotype rearrangements and centromere type transitions in human pathogenic yeasts of the CUG-Ser1 clade.

The human genome, comprising millions of pairs of bases, serves as the blueprint of life, encoding instructions for cellular processes. However, genomes are not merely linear sequences; rather, the complex of DNA and histones, known as chromatin, exhibits complex organization across various levels, which profoundly influence gene expression and cellular function. Central to understanding genome organization is the emerging field of three-dimensional (3D) genome studies. Utilizing advanced techniques such as Hi-C, researchers have unveiled non-random dispositions of genomic elements, highlighting their importance in transcriptional regulation and disease mechanisms. Topologically Associating Domains (TADs), that demarcate regions of chromatin with preferential internal interactions, play crucial roles in gene regulation and are increasingly implicated in various diseases such as cancer and schizophrenia. However, their role in Neurodevelopmental Disorders (NDDs) remains poorly understood. Here, we focus on TADs and 3D conservation across the evolution and between cell types in NDDs. The investigation into genome organization and its impact on disease has led to significant breakthroughs in understanding NDDs etiology such ASD (Autism Spectrum Disorder). By elucidating the wide spectrum of ASD manifestations, researchers aim to uncover the underlying genetic and epigenetic factors contributing to its heterogeneity. Moreover, studies linking TAD disruption to NDDs underscore the importance of spatial genome organization in maintaining proper brain development and function. In summary, this review highlights the intricate interplay between genome organization, transcriptional control, and disease pathology, shedding light on fundamental biological processes and offering insights into the mechanisms underlying NDDs like ASD.

Background The genome architecture mapping (GAM) technique can capture genome-wide chromatin interactions. However, besides the known systematic biases in the raw GAM data, we have found a new type of systematic bias. It is necessary to develop and evaluate effective normalization methods to remove all systematic biases in the raw GAM data. Results We have detected a new type of systematic bias, the fragment length bias, in the genome architecture mapping (GAM) data, which is significantly different from the bias of window detection frequency previously mentioned in the paper introducing the GAM method but is similar to the bias of distances between restriction sites existing in raw Hi-C data. We have found that the normalization method (a normalized variant of the linkage disequilibrium) used in the GAM paper is not able to effectively eliminate the new fragment length bias at 1 Mb resolution (slightly better at 30 kb resolution). We have developed an R package named normGAM for eliminating the new fragment length bias together with the other three biases existing in raw GAM data, which are the biases related to window detection frequency, mappability, and GC content. Five normalization methods have been implemented and included in the R package including Knight-Ruiz 2-norm (KR2, newly designed by us), normalized linkage disequilibrium (NLD), vanilla coverage (VC), sequential component normalization (SCN), and iterative correction and eigenvector decomposition (ICE). Conclusions Based on our evaluations, the five normalization methods can eliminate the four biases existing in raw GAM data, with VC and KR2 performing better than the others. We have observed that the KR2-normalized GAM data have a higher correlation with the KR-normalized Hi-C data on the same cell samples indicating that the KR-related methods are better than the others for keeping the consistency between the GAM and Hi-C experiments. Compared with the raw GAM data, the normalized GAM data are more consistent with the normalized distances from the fluorescence in situ hybridization (FISH) experiments. The source code of normGAM can be freely downloaded from http://dna.cs.miami.edu/normGAM/ .

Abstract Eukaryotic genomes are highly compacted in the cell nucleus. Two loci separated by a long linear distance can be brought into proximity in space through DNA-binding proteins and RNAs, which contributes profoundly to the regulation of gene expression. Recent technology advances have enabled the development and application of the chromosome conformation capture (3C) technique and a host of 3C-based methods that enable genome-scale investigations into changes in chromatin high-order structures during diverse physiological processes and diseases. In this review, we introduce 3C-based technologies and discuss how they can be utilized to glean insights into the impacts of three-dimensional (3D) genome organization in normal physiological and disease processes.

While long non-coding RNA (lncRNA) genes have attracted a lot of attention in the last decade, the focus regarding their mechanisms of action has been primarily on the RNA product of these genes. Recent work on several lncRNAs genes demonstrates that not only is the produced RNA species important, but also that transcription of the lncRNA locus alone can have regulatory functions. Like the functions of lncRNA transcripts, the mechanisms that underlie these genome-based functions are varied. Here we highlight some of these examples and provide an outlook on how the functional mechanisms of a lncRNA gene can be determined.

At the nuclear periphery, associations of chromatin with the nuclear lamina through lamina-associated domains (LADs) aid functional organization of the genome. We review the organization of LADs and provide evidence of LAD heterogeneity from cell ensemble and single-cell data. LADs are typically repressive environments in the genome; nonetheless, we discuss findings of lamin interactions with regulatory elements of active genes, and the role lamins may play in genome regulation. We address the relationship between LADs and other genome organizers, and the involvement of LADs in laminopathies. The current data lay the basis for future studies on the significance of lamin-chromatin interactions in health and disease.

Transposable element (TE) amplification has been recognized as a driving force mediating genome size expansion and evolution, but the consequences for shaping 3D genomic architecture remains largely unknown in plants. Here, we report reference-grade genome assemblies for three species of cotton ranging 3-fold in genome size, namely Gossypium rotundifolium (K2), G. arboreum (A2), and G. raimondii (D5), using Oxford Nanopore Technologies. Comparative genome analyses document the details of lineage-specific TE amplification contributing to the large genome size differences (K2, 2.44 Gb; A2, 1.62 Gb; D5, 750.19 Mb) and indicate relatively conserved gene content and synteny relationships among genomes. We found that approximately 17% of syntenic genes exhibit chromatin status change between active (“A”) and inactive (“B”) compartments, and TE amplification was associated with the increase of the proportion of A compartment in gene regions (∼7,000 genes) in K2 and A2 relative to D5. Only 42% of topologically associating domain (TAD) boundaries were conserved among the three genomes. Our data implicate recent amplification of TEs following the formation of lineage-specific TAD boundaries. This study sheds light on the role of transposon-mediated genome expansion in the evolution of higher-order chromatin structure in plants.

The DNA-binding protein CCCTC-binding factor (CTCF) and the cohesin complex function together to shape chromatin architecture in mammalian cells, but the molecular details of this process remain unclear. Here, we demonstrate that a 79-aa region within the CTCF N terminus is essential for cohesin positioning at CTCF binding sites and chromatin loop formation. However, the N terminus of CTCF fused to artificial zinc fingers was not sufficient to redirect cohesin to non-CTCF binding sites, indicating a lack of an autonomously functioning domain in CTCF responsible for cohesin positioning. BORIS (CTCFL), a germline-specific paralog of CTCF, was unable to anchor cohesin to CTCF DNA binding sites. Furthermore, CTCF–BORIS chimeric constructs provided evidence that, besides the N terminus of CTCF, the first two CTCF zinc fingers, and likely the 3D geometry of CTCF–DNA complexes, are also involved in cohesin retention. Based on this knowledge, we were able to convert BORIS into CTCF with respect to cohesin positioning, thus providing additional molecular details of the ability of CTCF to retain cohesin. Taken together, our data provide insight into the process by which DNA-bound CTCF constrains cohesin movement to shape spatiotemporal 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.