Integrating chromosome conformation and DNA repair in a computational framework to assess cell radiosensitivity.

The arrangement of chromosomes in the cell nucleus has implications for cell radiosensitivity. The development of new tools to utilize Hi-C chromosome conformation data in nanoscale radiation track structure simulations allows forinvestigation of this phenomenon. We have developed a framework employing Hi-C-based cell nucleus models in Monte Carlo radiation simulations, in conjunction with mechanistic models of DNA repair, to predict not only the initial radiation-induced DNA damage, but also the repair outcomes resulting from this damage, allowing us to investigate the role chromosome conformation plays in the biological outcome of radiation exposure.

Rearrangement of 3D genome organization in breast cancer epithelial - mesenchymal transition and metastasis organotropism.

Breast cancer cells exhibit organotropism during metastasis, showing preferential homing to certain organs such as bone, lung, liver, and brain. One potential explanation for this organotropic behavior is that cancer cells gain properties that enable thriving in certain microenvironments. Such specific metastatic traits may arise from gene regulation at the primary tumor site.

Deciphering Pre-existing and Induced 3D Genome Architecture Changes involved in Constricted Melanoma Migration.

Metastatic cancer cells traverse constricted spaces that exert forces on their nucleus and the genomic contents within. Cancerous tumors are highly heterogeneous and not all cells within them can achieve such a feat. Here, we investigated what initial genome architecture characteristics favor the constricted migratory ability of cancer cells and which arise only after passage through multiple constrictions.

Node features of chromosome structure networks and their connections to genome annotation.

The 3D conformations of chromosomes can encode biological significance, and the implications of such structures have been increasingly appreciated recently. Certain chromosome structural features, such as A/B compartmentalization, are frequently extracted from Hi-C pairwise genome contact information (physical association between different regions of the genome) and compared with linear annotations of the genome, such as histone modifications and lamina association. We investigate how additional properties of chromosome structure can be deduced using an abstract graph representation of the contact heatmap, and describe specific network properties that can have a strong connection with some of these biological annotations.

Chromosome compartmentalization: causes, changes, consequences, and conundrums.

The spatial segregation of the genome into compartments is a major feature of 3D genome organization. New data on mammalian chromosome organization across different conditions reveal important information about how and why these compartments form and change. A combination of epigenetic state, nuclear body tethering, physical forces, gene expression, and replication timing (RT) can all influence the establishment and alteration of chromosome compartments.

MASI enables fast model-free standardization and integration of single-cell transcriptomics data.

Single-cell transcriptomics datasets from the same anatomical sites generated by different research labs are becoming increasingly common. However, fast and computationally inexpensive tools for standardization of cell-type annotation and data integration are still needed in order to increase research inclusivity. To standardize cell-type annotation and integrate single-cell transcriptomics datasets, we have built a fast model-free integration method, named MASI (Marker-Assisted Standardization and Integration).

Prioritization of the concepts and skills in quantitative education for graduate students in biomedical science.

Substantial guidance is available on undergraduate quantitative training for biologists, including reports focused on biomedical science. Far less attention has been paid to the graduate curriculum and the particular challenges of the diversity of specialization within the life sciences. We propose an innovative approach to quantitative education that goes beyond recommendations of a course or set of courses or activities, derived from analysis of the expectations for students in particular programs.

Differential contributions of nuclear lamina association and genome compartmentalization to gene regulation.

Chromatin regions that interact with the nuclear lamina are often heterochromatic, repressed in gene expression, and in the spatial B compartment. However, exceptions to this trend allow us to examine the relative impact of lamin association and spatial compartment on gene regulation. Here, we compared lamin association, gene expression, Hi-C, and histone mark datasets from cell lines representing different states of differentiation across different cell-type lineages.

Amorphous calcium phosphate-coated surfaces as a model for bone microenvironment in prostate cancer.

Unlabelled: Bone metastasis remains one of the biggest challenges in the treatment of prostate cancer, and other solid tumors such as breast, lung, and colon. Modeling a complex microenvironment in-vitro, such as the bone niche, requires interrogation of cell-cell interactions, specific extracellular matrix proteins and a high calcium environment. Here, we present a fast and cost-effective system in which commercially available, non-adhesive, cell culture vessels are coated with amorphous calcium phosphate (ACP) as a surrogate for bone matrix.

Fast model-free standardization and integration of single-cell transcriptomics data.

Single-cell transcriptomics datasets from the same anatomical sites generated by different research labs are becoming increasingly common. However, fast and computationally inexpensive tools for standardization of cell-type annotation and data integration are still needed in order to increase research inclusivity. To standardize cell-type annotation and integrate single-cell transcriptomics datasets, we have built a fast model-free integration method, named MASI (Marker-Assisted Standardization and Integration).

Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification.

The expression of a mutant Lamin A, progerin, in Hutchinson-Gilford Progeria Syndrome leads to alterations in genome architecture, nuclear morphology, epigenetic states, and altered phenotypes in all cells of the mesenchymal lineage. Here, we report a comprehensive analysis of the transcriptional status of patient derived HGPS fibroblasts, including nine cell lines not previously reported, in comparison with age-matched controls, adults, and old adults. We find that Progeria fibroblasts carry abnormal transcriptional signatures, centering around several functional hubs: DNA maintenance and epigenetics, bone development and homeostasis, blood vessel maturation and development, fat deposition and lipid management, and processes related to muscle growth.

sciCAN: single-cell chromatin accessibility and gene expression data integration via cycle-consistent adversarial network.

The boom in single-cell technologies has brought a surge of high dimensional data that come from different sources and represent cellular systems from different views. With advances in these single-cell technologies, integrating single-cell data across modalities arises as a new computational challenge. Here, we present an adversarial approach, sciCAN, to integrate single-cell chromatin accessibility and gene expression data in an unsupervised manner.

Characterizing the variation in chromosome structure ensembles in the context of the nuclear microenvironment.

Inside the nucleus, chromosomes are subjected to direct physical interaction between different components, active forces, and thermal noise, leading to the formation of an ensemble of three-dimensional structures. However, it is still not well understood to what extent and how the structural ensemble varies from one chromosome region or cell-type to another. We designed a statistical analysis technique and applied it to single-cell chromosome imaging data to reveal the heterogeneity of individual chromosome structures.

Constricted migration is associated with stable 3D genome structure differences in cancer cells.

To spread from a localized tumor, metastatic cancer cells must squeeze through constrictions that cause major nuclear deformations. Since chromosome structure affects nucleus stiffness, gene regulation, and DNA repair, here, we investigate the relationship between 3D genome structure and constricted migration in cancer cells. Using melanoma (A375) cells, we identify phenotypic differences in cells that have undergone multiple rounds of constricted migration.

Diagonal integration of multimodal single-cell data: potential pitfalls and paths forward.

Diagonal integration of multimodal single-cell data emerges as a trending topic. However, empowering diagonal methods for novel biological discoveries requires bridging huge gaps. Here, we comment on potential risks and future directions of diagonal integration for multimodal single-cell data.

SnapShot: Chromosome organization.

Chromosomes in higher eukaryotes are folded at different length scales into loop extrusion domains, spatial compartments, and chromosome territories and exhibit interactions with nuclear structures such as the lamina. Microscopic methods can probe this structure by measuring positions of chromosomes in the nuclear space in individual cells, while sequencing-based contact capture approaches can report the frequency of contacts of different regions within these structural layers. To view this SnapShot, open or download the PDF.

Loops, topologically associating domains, compartments, and territories are elastic and robust to dramatic nuclear volume swelling.

Layers of genome organization are becoming increasingly better characterized, but less is known about how these structures respond to perturbation or shape changes. Low-salt swelling of isolated chromatin fibers or nuclei has been used for decades to investigate the structural properties of chromatin. But, visible changes in chromatin appearance have not been linked to known building blocks of genome structure or features along the genome sequence.

Voices on technology: The molecular biologists' ever-expanding toy box.

With the focus on technology for this issue of Molecular Cell, a group of scientists working in different areas of molecular biology provide their perspective on the most recent important technological advance in their field, where the field is lacking, and their wish list for future technology development.

Chromosome compartmentalization alterations in prostate cancer cell lines model disease progression.

Prostate cancer aggressiveness and metastatic potential are influenced by gene expression and genomic aberrations, features that can be influenced by the 3D structure of chromosomes inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, from normal epithelium to bone metastasis. We describe spatial compartment identity (A-open versus B-closed) changes with progression in these cell lines and their relation to gene expression changes in both cell lines and patient samples.

SMILE: mutual information learning for integration of single-cell omics data.

Motivation: Deep learning approaches have empowered single-cell omics data analysis in many ways and generated new insights from complex cellular systems. As there is an increasing need for single-cell omics data to be integrated across sources, types and features of data, the challenges of integrating single-cell omics data are rising. Here, we present an unsupervised deep learning algorithm that learns discriminative representations for single-cell data via maximizing mutual information, SMILE (Single-cell Mutual Information Learning).

CoSTA: unsupervised convolutional neural network learning for spatial transcriptomics analysis.

Background: The rise of spatial transcriptomics technologies is leading to new insights about how gene regulation happens in a spatial context. Determining which genes are expressed in similar spatial patterns can reveal gene regulatory relationships across cell types in a tissue. However, many current analysis methods do not take full advantage of the spatial organization of the data, instead treating pixels as independent features.

Radiation-induced DNA damage and repair effects on 3D genome organization.

The three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells.

Inferring chromosome radial organization from Hi-C data.

Background: The nonrandom radial organization of eukaryotic chromosome territories (CTs) inside the nucleus plays an important role in nuclear functional compartmentalization. Increasingly, chromosome conformation capture (Hi-C) based approaches are being used to characterize the genome structure of many cell types and conditions. Computational methods to extract 3D arrangements of CTs from this type of pairwise contact data will thus increase our ability to analyze CT organization in a wider variety of biological situations.

Using contact statistics to characterize structure transformation of biopolymer ensembles.

As a unique subset of functional polymers, many biopolymers have a set of well-defined three-dimensional (3D) structural characteristics that can be described by spatial contacts between monomers. Statistical analysis of the contacts has been extremely productive in characterizing the biopolymer structural ensemble, such as for 3D chromosome structures. Often, native contacts and compartment structures are the focus of the studies, while the generic polymer aspect, such as the overall decaying of contacts with increasing sequence distance, is analyzed separately or preemptively removed.