A prominent organizational feature of bacterial chromosomes was revealed by Hi-C experiments, indicating anomalously high contacts between the left and right chromosomal arms. These long-range contacts have been attributed to various nucleoid-associated proteins, including the ATPase Structural Maintenance of Chromosomes (SMC) condensin. Although the molecular structure of these ATPases has been mapped in detail, it still remains unclear by which physical mechanisms they collectively generate long-range chromosomal contacts. Here, we develop a computational model that captures the subtle interplay between molecular-scale activity of slip-links and large-scale chromosome organization. We first consider a scenario in which the ATPase activity of slip-links regulates their DNA-recruitment near the origin of replication, while the slip-link dynamics is assumed to be diffusive. We find that such diffusive slip-links can collectively organize the entire chromosome into a state with aligned arms, but not within physiological constraints. However, slip-links that include motor activity are far more effective at organizing the entire chromosome over all length-scales. The persistence of motor slip-links at physiological densities can generate large, nested loops and drive them into the bulk of the DNA. Finally, our model with motor slip-links can quantitatively account for the rapid arm-arm alignment of chromosomal arms observed .
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6228497 | PMC |
http://dx.doi.org/10.1098/rsif.2018.0495 | DOI Listing |
Proc Natl Acad Sci U S A
February 2025
Courant Institute for Mathematical Sciences and Department of Biology, New York University, New York, NY 10012.
Accurate chromosome segregation in mitosis depends on proper connections of sister chromatids, through microtubules, to the opposite poles of the early mitotic spindle. Transiently, many inaccurate connections are formed and rapidly corrected throughout the mitotic stages, but a small number of merotelic connections, in which a chromatid is connected to both spindle poles, remain lagging at the spindle's equator in anaphase. Most of the lagging chromatids are eventually moved to one or the other pole, likely by a combination of microtubules' turnover and the brute force of pulling by the microtubules' majority from the one pole against the microtubules' minority from the other pole.
View Article and Find Full Text PDFWe lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into repetitive sequences, up to 1697 per cell line, which enables generating large-scale deletions, inversions, translocations, and circular DNA. Recombinase induction produced more than 100 stochastic megabase-sized rearrangements in each cell.
View Article and Find Full Text PDFScience
January 2025
Department of Genome Sciences, University of Washington, Seattle, WA, USA.
Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) methods to generate, map, and characterize SVs in model systems are underdeveloped. To address these challenges, we developed Genome-Shuffle-seq, a method that enables the multiplex generation and mapping of thousands of SVs (deletions, inversions, translocations, and extrachromosomal circles) throughout mammalian genomes. We also demonstrate the co-capture of SV identity with single-cell transcriptomes, facilitating the measurement of SV impact on gene expression.
View Article and Find Full Text PDFNucleic Acids Res
January 2025
Department of Medicine, UofL Health Brown Cancer Center, University of Louisville, Louisville KY, 505 S Hancock St, Louisville, KY 40202, United States.
Time-resolved small-angle X-ray experiments are reported here that capture and quantify a previously unknown rapid collapse of the unfolded oligonucleotide as an early step in the folding of hybrid 1 and hybrid 2 telomeric G-quadruplex structures. The rapid collapse, initiated by a pH jump, is characterized by an exponential decrease in the radius of gyration from 24.3 to 12.
View Article and Find Full Text PDFSci Rep
January 2025
MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
Bulk ATAC-seq assays have been used to map and profile the chromatin accessibility of regulatory elements such as enhancers, promoters, and insulators. This has provided great insight into the regulation of gene expression in many cell types in a variety of organisms. To date, ATAC-seq has most often been used to provide an average evaluation of chromatin accessibility in populations of cells.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!