43 research outputs found
Integrating transposable elements in the 3D genome
Chromosome organisation is increasingly recognised as an essential component of genome regulation, cell fate and cell health. Within the realm of transposable elements (TEs) however, the spatial information of how genomes are folded is still only rarely integrated in experimental studies or accounted for in modelling. Whilst polymer physics is recognised as an important tool to understand the mechanisms of genome folding, in this commentary we discuss its potential applicability to aspects of TE biology. Based on recent works on the relationship between genome organisation and TE integration, we argue that existing polymer models may be extended to create a predictive framework for the study of TE integration patterns. We suggest that these models may offer orthogonal and generic insights into the integration profiles (or "topography") of TEs across organisms. In addition, we provide simple polymer physics arguments and preliminary molecular dynamics simulations of TEs inserting into heterogeneously flexible polymers. By considering this simple model, we show how polymer folding and local flexibility may generically affect TE integration patterns. The preliminary discussion reported in this commentary is aimed to lay the foundations for a large-scale analysis of TE integration dynamics and topography as a function of the three-dimensional host genome
In the absence of cancer registry data, is it sensible to assess incidence using hospital separation records?
BACKGROUND: Within the health literature, a major goal is to understand distribution of service utilisation by social location. Given equivalent access, differential incidence leads to an expectation of differential service utilisation. Cancer incidence is differentially distributed with respect to socioeconomic status. However, not all jurisdictions have incidence registries, and not all registries allow linkage with utilisation records. The British Columbia Linked Health Data resource allows such linkage. Consequently, we examine whether, in the absence of registry data, first hospitalisation can act as a proxy measure for incidence, and therefore as a measure of need for service. METHODS: Data are drawn from the British Columbia Linked Health Data resource, and represent 100% of Vancouver Island Health Authority cancer registry and hospital records, 1990–1999. Hospital separations (discharges) with principal diagnosis ICD-9 codes 140–208 are included, as are registry records with ICDO-2 codes C00-C97. Non-melanoma skin cancer (173/C44) is excluded. Lung, colorectal, female breast, and prostate cancers are examined separately. We compare registry and hospital annual counts and age-sex distributions, and whether the same individuals are represented in both datasets. Sensitivity, specificity and predictive values are calculated, as is the kappa statistic for agreement. The registry is designated the gold standard. RESULTS: For all cancers combined, first hospitalisation counts consistently overestimate registry incidence counts. From 1995–1999, there is no significant difference between registry and hospital counts for lung and colorectal cancer (p = 0.42 and p = 0.56, respectively). Age-sex distribution does not differ for colorectal cancer. Ten-year period sensitivity ranges from 73.0% for prostate cancer to 84.2% for colorectal cancer; ten-year positive predictive values range from 89.5% for female breast cancer to 79.35% for prostate cancer. Kappa values are consistently high. CONCLUSION: Claims and registry databases overlap with an appreciable proportion of the same individuals. First hospital separation may be considered a proxy for incidence with reference to colorectal cancer since 1995. However, to examine equity across cancer health services utilisation, it is optimal to have access to both hospital and registry files
Physical Principles of Retroviral Integration in the Human Genome
Some retroviruses, including HIV, insert their DNA in a non-random manner in the host genome through a poorly understood selection mechanism. Here the authors develop a biophysical model of retroviral integration, identifying previously unnoticed universal principles that regulate this phenomenon
Assembly PCR synthesis of optimally designed, compact, multi-responsive promoters suited to gene therapy application
MRC-DTA studentship award
British Pharmacological Society Integrative Awar
Active and poised promoter states drive folding of the extended HoxB locus in mouse embryonic stem cells
Gene expression states influence the three-dimensional conformation of the genome through poorly understood mechanisms. Here, we investigate the conformation of the murine HoxB locus, a gene-dense genomic region containing closely spaced genes with distinct activation states in mouse embryonic stem (ES) cells. To predict possible folding scenarios, we performed computer simulations of polymer models informed with different chromatin occupancy features, which define promoter activation states or CTCF binding sites. Single cell imaging of the locus folding was performed to test model predictions. While CTCF occupancy alone fails to predict the in vivo folding at genomic length scale of 10 kb, we found that homotypic interactions between active and Polycomb-repressed promoters co-occurring in the same DNA fibre fully explain the HoxB folding patterns imaged in single cells. We identify state-dependent promoter interactions as major drivers of chromatin folding in gene-dense regions
Protein/DNA interactions in complex DNA topologies: expect the unexpected
DNA supercoiling results in compacted DNA structures that can bring distal sites into close proximity. It also changes the local structure of the DNA, which can in turn influence the way it is recognised by drugs, other nucleic acids and proteins. Here, we discuss how DNA supercoiling and the formation of complex DNA topologies can affect the thermodynamics of DNA recognition. We then speculate on the implications for transcriptional control and the three-dimensional organisation of the genetic material, using examples from our own simulations and from the literature. We introduce and discuss the concept of coupling between the multiple length-scales associated with hierarchical nuclear structural organisation through DNA supercoiling and topology