Frank Alber

Frank Alber
University of California, Los Angeles | UCLA · Department of Microbiology, Immunology, and Molecular Genetics

About

121
Publications
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Publications

Publications (121)
Article
Full-text available
A multitude of sequencing-based and microscopy technologies provide the means to unravel the relationship between the three-dimensional organization of genomes and key regulatory processes of genome function. Here, we develop a multimodal data integration approach to produce populations of single-cell genome structures that are highly predictive fo...
Article
New technological advances in integrated imaging, sequencing-based assays, and computational analysis have revolutionized our view of genomes in terms of their structure and dynamics in space and time. These advances promise a deeper understanding of genome functions and mechanistic insights into how the nucleus is spatially organized and functions...
Preprint
A multitude of sequencing-based and microscopy technologies provide the means to unravel the relationship between the three-dimensional (3D) organization of genomes and key regulatory processes of genome function. However, it remains a major challenge to systematically integrate all available data sources to characterize the nuclear organization of...
Article
Our understanding of how genomic DNA is tightly packed inside the nucleus, yet is still accessible for vital cellular processes, has grown dramatically over recent years with advances in microscopy and genomics technologies. Computational methods have played a pivotal role in the structural interpretation of experimental data, which helped unravel...
Preprint
The folding and subnuclear compartmentalization of chromosomes relative to nuclear bodies is an integral part of gene function. However, mapping the three-dimensional (3D) organization of all genes, in single cells, on a genome-wide scale remains a major challenge. Here, we demonstrate that data-driven population-based modeling, from ensemble Hi-C...
Article
Full-text available
Cell-free DNA (cfDNA) is attractive for many applications, including detecting cancer, identifying the tissue of origin, and monitoring. A fundamental task underlying these applications is SNV calling from cfDNA, which is hindered by the very low tumor content. Thus sensitive and accurate detection of low-frequency mutations (<5%) remains challengi...
Article
Cryo-electron tomography provides the opportunity for unsupervised discovery of endogenous complexes in situ. This process usually requires particle picking, clustering and alignment of subtomograms to produce an average structure of the complex. When applied to heterogeneous samples, template-free clustering and alignment of subtomograms can poten...
Article
Full-text available
Characterizing relationships between cell structures and functions requires mesoscale mapping of intact cells showing subcellular rearrangements following stimulation; however, current approaches are limited in this regard. Here, we report a unique application of soft x-ray tomography to generate three-dimensional reconstructions of whole pancreati...
Conference Paper
Liquid biopsy using cell-free DNA (cfDNA) is attractive for a wide range of clinical applications, including cancer detection, locating, and monitoring. However, developing these applications requires precise and sensitive calling of somatic single nucleotide variations (SNVs) from cfDNA sequencing data. To date, no SNV caller comprehensively addre...
Preprint
Full-text available
Cryo-electron tomography provides the opportunity for unsupervised discovery of endogenous complexes in situ. This process usually requires particle picking, clustering and alignment of subtomograms to produce an average structure of the complex. When applied to heterogeneous samples, template-free clustering and alignment of subtomograms can poten...
Preprint
Full-text available
Liquid biopsy using cell-free DNA (cfDNA) is attractive for a wide range of clinical applications, including cancer detection, locating, and monitoring. However, developing these applications requires precise and sensitive calling of somatic single nucleotide variations (SNVs) from cfDNA sequencing data. To date, no SNV caller addresses all the spe...
Article
Electron cryotomography enables 3D visualization of cells in a near-native state at molecular resolution. The produced cellular tomograms contain detailed information about a plethora of macromolecular complexes, their structures, abundances, and specific spatial locations in the cell. However, extracting this information in a systematic way is ver...
Article
Full-text available
Packaging of the genome in the nucleus is a non-random process that is thought to directly contribute to cell type-specific transcriptomes, although this hypothesis remains untested. Epigenome architecture, as assayed by chromatin conformation capture techniques, such as Hi-C, has recently been described in the mammalian cardiac myocyte and found t...
Data
List of genes with significant (q < 0.01) promoter-TES Fit-Hi-C interactions in the heart.
Data
Movie of cardiac and liver genomes shows Figure 7 in 360 degrees. In both heart and liver nuclei, computational models generated using PGS reveal organization of topologically associating domains (TADs) within chromosomes in 3D space (top, All chr), as well as interactions between TADs of individual chromosomes (bottom, chr1 and chr2 shown as examp...
Data
Radial positions of TADs differ between heart and liver. Across each chromosome, average radial positions of TADs are shown as solid lines (heart in red, liver in blue), with the positions of heart- (red points) and liver-specific genes (blue points) superimposed. The y-axis shows average radial position (0 is the center of the nucleus, 1 indicates...
Data
List of genes with significant (q < 0.01) promoter-TES Fit-Hi-C interactions in the liver.
Data
Comparison between contact probability heatmaps from experiment and structural models for heart (left) and liver (right). Each bin in the heatmap represents a TAD and each pixel represents the contact probability between 2 TADs. The lower triangle part shows the contact probability from experiment and the upper triangle shows the contact probabilit...
Article
Full-text available
The detection of tumor-derived cell-free DNA in plasma is one of the most promising directions in cancer diagnosis. The major challenge in such an approach is how to identify the tiny amount of tumor DNAs out of total cell-free DNAs in blood. Here we propose an ultrasensitive cancer detection method, termed 'CancerDetector', using the DNA methylati...
Article
Full-text available
Chromatin organization is highly dynamic and regulates transcription. Upon transcriptional activation, chromatin is remodeled and referred to as "open", but quantitative and dynamic data of this decompaction process are lacking. Here, we have developed a quantitative high-resolution microscopy assay in living yeast cells to visualize and quantify c...
Preprint
Full-text available
Chromatin organization is highly dynamic and regulates transcription. Upon transcriptional activation, chromatin is remodeled and referred to as “open”, but quantitative and dynamic data of this decompaction process are lacking. Here, we have developed a quantitative high-resolution microscopy assay in living yeast cells to visualize and quantify c...
Article
Chromosome conformation capture technologies such as Hi-C are widely used to investigate the spatial organization of genomes. Because genome structures can vary considerably between individual cells of a population, interpreting ensemble-averaged Hi-C data can be challenging, in particular for long-range and interchromosomal interactions. We pionee...
Article
The construction of a predictive model of an entire eukaryotic cell that describes its dynamic structure from atomic to cellular scales is a grand challenge at the intersection of biology, chemistry, physics, and computer science. Having such a model will open new dimensions in biological research and accelerate healthcare advancements. Developing...
Chapter
Full-text available
Heterochromatin is mostly composed of long stretches of repeated DNA sequences prone to ectopic recombination during double-strand break (DSB) repair. In Drosophila, "safe" homologous recombination (HR) repair of heterochromatic DSBs relies on a striking relocalization of repair sites to the nuclear periphery. Central to understanding heterochromat...
Preprint
Full-text available
Heterochromatin is mostly composed of long stretches of repeated DNA sequences prone to ectopic recombination during double-strand break (DSB) repair. In Drosophila , ‘safe’ homologous recombination (HR) repair of heterochromatic DSBs relies on a striking relocalization of repair sites to the nuclear periphery. Central to understanding heterochroma...
Article
A wide variety of experimental techniques can be used for understanding the precise molecular mechanisms underlying the activities of cellular assemblies. The inherent limitations of a single experimental technique often requires integration of data from complementary approaches to gain sufficient insights into the assembly structure and function....
Article
Full-text available
BACKGROUND: Genome structures are dynamic and non-randomly organized in the nucleus of higher eukaryotes. To maximize the accuracy and coverage of three-dimensional genome structural models, it is important to integrate all available sources of experimental information about a genome's organization. It remains a major challenge to integrate such d...
Poster
Full-text available
Revealing the Native Molecular Architecture of the Nuclear Periphery using Cryo-Focused-Ion-Beam Milling, Light Microscopy and Electron Tomography - Volume 23 Issue S1 - Elizabeth Villa, Reika Watanabe, Robert Buschauer, Kanika Khanna, Vinson Lam, Jitin Singla, Frank Alber
Preprint
Full-text available
Viruses have evolved a variety of mechanisms to interact with host cells for their adaptive benefits, including subverting host immune responses and hijacking host DNA replication/transcription machineries [1–3]. Although interactions between viral and host proteins have been studied extensively, little is known about how the vial genome may intera...
Article
Cryo-electron tomography (cryo-ET) captures the 3D electron density distribution of macromolecular complexes in close to native state. With the rapid advance of cryo-ET acquisition technologies, it is possible to generate large numbers (>100,000) of subtomograms, each containing a macromolecular complex. Often, these subtomograms represent a hetero...
Article
Full-text available
We propose a probabilistic method, CancerLocator, which exploits the diagnostic potential of cell-free DNA by determining not only the presence but also the location of tumors. CancerLocator simultaneously infers the proportions and the tissue-of-origin of tumor-derived cell-free DNA in a blood sample using genome-wide DNA methylation data. CancerL...
Article
Full-text available
Neutrophils are responsible for the first line of defense against invading pathogens. Their nuclei are uniquely structured as multiple lobes that establish a highly constrained nuclear environment. Here we found that neutrophil differentiation was not associated with large-scale changes in the number and sizes of topologically associating domains (...
Preprint
Hi-C technologies are widely used to investigate the spatial organization of genomes. However, the structural variability of the genome is a great challenge to interpreting ensemble-averaged Hi-C data, particularly for long-range/interchromosomal interactions. We pioneered a probabilistic approach for generating a population of distinct diploid 3D...
Article
Full-text available
Genome structures are dynamic and non-randomly organized in the nucleus of higher eukaryotes. To maximize the accuracy and coverage of 3D genome structural models, it is important to integrate all available sources of experimental information about a genome's organization. It remains a major challenge to integrate such data from various complementa...
Preprint
Full-text available
Neutrophils are responsible for the first line of defense against invading pathogens. Their nuclei are uniquely structured as multiple lobes that establish a highly constrained nuclear environment. Here we found that neutrophil differentiation was not associated with large-scale changes in the number and sizes of topologically associating domains....
Article
Full-text available
Background Cryo-electron tomography is an important tool to study structures of macromolecular complexes in close to native states. A whole cell cryo electron tomogram contains structural information of all its macromolecular complexes. However, extracting this information remains challenging, and relies on sophisticated image processing, in partic...
Article
Full-text available
Three-dimensional (3D) genome structures vary from cell to cell even in an isogenic sample. Unlike protein structures, genome structures are highly plastic, posing a significant challenge for structure-function mapping. Here we report an approach to comprehensively identify 3D chromatin clusters that each occurs frequently across a population of ge...
Data
Supplementary Figures 1-11, Supplementary Tables 1-9, Supplementary Notes 1-8 and Supplementary References
Article
Full-text available
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 probabilis...
Preprint
This preprint is available on arXiv.org as well: https://arxiv.org/abs/1512.09347 This is a method to find reoccuring patterns in the single cell cryo-electron tomograms. The paper is under review at Structure.
Article
Full-text available
The organization of the genome is nonrandom and important for correct function. Specifically, the nuclear envelope plays a critical role in gene regulation. It generally constitutes a repressive environment, but several genes, including the GAL locus in budding yeast, are recruited to the nuclear periphery on activation. Here, we combine imaging an...
Article
Full-text available
Cryo-electron tomography enables 3D visualization of cells in a near native state at molecular resolution. The produced cellular tomograms contain detailed information about all macromolecular complexes, their structures, their abundances and their specific spatial locations in the cell. However, extracting this information is very challenging and...
Article
Full-text available
Genome-wide proximity ligation assays allow the identification of chromatin contacts at unprecedented resolution. Several studies reveal that mammalian chromosomes are composed of topological domains (TDs) in sub-mega base resolution, which appear to be conserved across cell types and to some extent even between organisms. Identifying topological d...
Article
Full-text available
We have developed a genetic algorithm for building macromolecular complexes using only a 3D-electron microscopy density map and the atomic structures of the relevant components. For efficient sampling the method uses map feature points calculated by vector quantization. The fitness function combines a mutual information score that quantifies the go...
Article
Full-text available
We studied the 3D structural organization of the fission yeast genome, which emerges from the tethering of heterochromatic regions in otherwise randomly configured chromosomes represented as flexible polymer chains in an nuclear environment. This model is sufficient to explain in a statistical manner many experimentally determined distinctive featu...
Article
Full-text available
Unlabelled: Genome-wide proximity ligation assays, e.g. Hi-C and its variant TCC, have recently become important tools to study spatial genome organization. Removing biases from chromatin contact matrices generated by such techniques is a critical preprocessing step of subsequent analyses. The continuing decline of sequencing costs has led to an e...
Article
Full-text available
A detailed description of macromolecular assemblies in multiple conformational states can be very valuable for understanding cellular processes. At present, structural determination of most assemblies in different biologically relevant conformations cannot be achieved by a single technique and thus requires an integrative approach that combines inf...
Article
Full-text available
Cryo-electron tomography allows the imaging of macromolecular complexes in near living conditions. To enhance the nominal resolution of a structure it is necessary to align and average individual subtomograms each containing identical complexes. However, if the sample of complexes is heterogeneous, it is necessary to first classify subtomograms int...
Article
Knowledge about the 3D organization of the genome will offer great insights into how cells retrieve and process the genetic information. Knowing the spatial probability distributions of individual genes will provide insights into gene regulatory and replication processes, and fill in the missing links between epigenomics, functional genomics, and s...
Article
Two studies plant a signpost on the road toward a robust and detailed chromatin interaction map.
Conference Paper
Full-text available
Background / Purpose: Genome structures are inherently plastic, with large cell-to-cell variations among cells of the same type and under the same condition.To address the challenge of modeling highly variable genome structures, we propose a population-based modeling approach, where we construct a large population of 3D genome models. Our work de...
Article
Full-text available
Cryo-electron tomography emerges as an important component for structural system biology. It not only allows the structural characterization of macromolecular complexes, but also the detection of their cellular localizations in near living conditions. However, the method is hampered by low resolution, missing data and low signal-to-noise ratio (SNR...
Article
Full-text available
Particle-based Brownian dynamics simulations offer the opportunity to not only simulate diffusion of particles but also the reactions between them. They therefore provide an opportunity to integrate varied biological data into spatially explicit models of biological processes, such as signal transduction or mitosis. However, particle based reaction...
Article
Full-text available
In this paper we show that tethering of heterochromatic regions to nuclear landmarks and random encounters of chromosomes in the confined nuclear volume are sufficient to explain the higher-order organization of the budding yeast genome. We have quantitatively characterized the contact patterns and nuclear territories that emerge when chromosomes a...