Topoisomerase II beta interacts with cohesin and CTCF at topological domain borders

BACKGROUND: Type II DNA topoisomerases (TOP2) regulate DNA topology by generating transient double stranded breaks during replication and transcription. Topoisomerase II beta (TOP2B) facilitates rapid gene expression and functions at the later stages of development and differentiation. To gain new insight into the genome biology of TOP2B, we used proteomics (BioID), chromatin immunoprecipitation, and high-throughput chromosome conformation capture (Hi-C) to identify novel proximal TOP2B protein interactions and characterize the genomic landscape of TOP2B binding at base pair resolution. RESULTS: Our human TOP2B proximal protein interaction network included members of the cohesin complex and nucleolar proteins associated with rDNA biology. TOP2B associates with DNase I hypersensitivity sites, allele-specific transcription factor (TF) binding, and evolutionarily conserved TF binding sites on the mouse genome. Approximately half of all CTCF/cohesion-bound regions coincided with TOP2B binding. Base pair resolution ChIP-exo mapping of TOP2B, CTCF, and cohesin sites revealed a striking structural ordering of these proteins along the genome relative to the CTCF motif. These ordered TOP2B-CTCF-cohesin sites flank the boundaries of topologically associating domains (TADs) with TOP2B positioned externally and cohesin internally to the domain loop. CONCLUSIONS: TOP2B is positioned to solve topological problems at diverse cis-regulatory elements and its occupancy is a highly ordered and prevalent feature of CTCF/cohesin binding sites that flank TADs

What prompts young adults in Ireland to attend health services for STI testing?

<p>Abstract</p> <p>Background</p> <p>In-depth understanding of the factors that prompt young adults to attend health services for sexually transmitted infection (STI) testing are needed to underpin sexual health programes. We conducted a qualitative study to identify and explore why young adults (18–29 years) in Ireland attended specialist and community health services for STI testing; the factors that supported/undermined their decisions to seek STI testing; and any factors that led to delay in seeking STI testing.</p> <p>Methods</p> <p>Semi-structured interviews with 30 adults (21 women, 9 men). Young adults were recruited from General Practice (GP) practices, Third Level College health services, Family Planning clinics and specialist STI treatment services for men who have sex with men (MSM). Interview questions examined why respondents decided to go for STI testing, whether they acted upon this desire immediately or decided to wait, and what they felt were important barriers/enablers to their health-seeking attempts. Interviews were thematically analyzed using standard qualitative techniques.</p> <p>Results</p> <p>Respondents sought STI testing for one of four reasons: they had reached a transitional moment in their lives (they were either about to stop using condoms with their sexual partner or were emerging from a period of their lives where they had a series of risky sexual relationships); they had had unprotected sex with a casual partner; they had symptoms of infection; and/or they were required to do so by their employer. Catalytic factors included media and government health promotion campaigns and knowing someone with an STI. However, many respondents delayed seeking testing. Reasons included respondents' concerns about stigma and that they would be judged by healthcare professionals, and feelings of invulnerability. Importantly, several respondents who waited up to four weeks to make an appointment after their initial decision to seek STI testing did not view this as delay.</p> <p>Conclusion</p> <p>Sexual health promotion campaigns for young people should address the reasons why they delay testing, specifically through measures to avoid stigma (supply-side) and reassure young adults (demand-side). Strategies to increase testing-uptake should focus on these four key opportunities – young adults leaving relationships, those entering relationships where condoms will not be used, those who have had unprotected sex and those with STI-related symptoms.</p

Nonequilibrium Chromosome Looping via Molecular Slip Links

We propose a model for the formation of chromatin loops based on the diffusive sliding of a DNA-bound factor which can dimerise to form a molecular slip-link. Our slip-links mimic the behaviour of cohesin-like molecules, which, along with the CTCF protein, stabilize loops which organize the genome. By combining 3D Brownian dynamics simulations and 1D exactly solvable non-equilibrium models, we show that diffusive sliding is sufficient to account for the strong bias in favour of convergent CTCF-mediated chromosome loops observed experimentally. Importantly, our model does not require any underlying, and energetically costly, motor activity of cohesin. We also find that the diffusive motion of multiple slip-links along chromatin may be rectified by an intriguing ratchet effect that arises if slip-links bind to the chromatin at a preferred "loading site". This emergent collective behaviour is driven by a 1D osmotic pressure which is set up near the loading point, and favours the extrusion of loops which are much larger than the ones formed by single slip-links.Comment: 37 pages, 12 figures, Supplementary Movies can be downloaded at http://www2.ph.ed.ac.uk/~dmarendu/Cohesin/SMX.mp4; with X=1, 2 or

Syphilis epidemiology in Norway, 1992-2008: resurgence among men who have sex with men

<p>Abstract</p> <p>Background</p> <p>In recent years, the number of syphilis cases has stabilised in many countries of Western Europe, however several countries have reported increases among men who have sex with men (MSM). The aim of this article was to describe the epidemiology of early syphilis in Norway in 1992-2008.</p> <p>Methods</p> <p>Cases of early syphilis and congenital syphilis reported to the Norwegian Surveillance System for Communicable Diseases (MSIS) 1992-2008 were described by route of transmission, gender, age, birthplace, stage of disease, HIV co-infection, source partner and place of infection.</p> <p>Results</p> <p>The incidence of reported syphilis ranged from 0.05 (1992) to 1.50 (2002) per 100 000 person-years. Of 562 cases reported to MSIS during the study period, 62% were men infected by another man. The proportion of those, infected homosexually increased from 0 (1992-1994) to 77% (2008). Most of them were Norwegians (83%). The proportion of HIV co-infection among homosexually infected increased over time and reached 39% in 2008. The majority reported being infected by a casual partner (73%) and in the municipality of Oslo (72%). Of 152 heterosexually infected men 64% were Norwegians; 51% were infected by casual contacts and 20% by commercial sex workers; 73% were infected abroad. Among 56 women, 57% were Norwegians, 57% were infected by a steady partner and 40% were infected abroad. Almost half (46%) were diagnosed in the early latent stage. Four cases had congenital syphilis, two of whom were adopted from abroad.</p> <p>Conclusions</p> <p>Syphilis is rare in Norway, but MSM represent almost two thirds of cases. The increase of HIV co-infected cases among MSM may enhance transmission of both infections. We recommend sexually active MSM to be tested for syphilis 2-4 times a year. Due to its variable clinical course, syphilis might be difficult to recognise at an early stage among women in a low-prevalence population. We estimate current practice of prenatal screening in Norway as sufficient.</p

Urine-based testing for Chlamydia trachomatis among young adults in a population-based survey in Croatia: Feasibility and prevalence

<p>Abstract</p> <p>Background</p> <p>We assessed the feasibility of collecting urine samples for testing on genital <it>Chlamydia trachomatis </it>infection in a population-based survey, and prevalence of this infection among young people aged 18-25 in Croatia. In Croatia, as in the other countries of Eastern Europe, there is a lack of data on prevalence of <it>C trachomatis </it>in the general population, including young adults.</p> <p>Methods</p> <p>We sampled participants using a nationally representative, multi-stage stratified probability sample of young men and women. Detection of <it>C trachomatis </it>DNA in urine samples was performed by using a real-time PCR assay COBAS^®TaqMan^®CT Test, v2.0.</p> <p>Results</p> <p>Overall, 1005 young adults participated in the behavioural part of the survey, and 27.9% men and 37.5% women who were sexually experienced agreed to provide urine samples for testing on <it>C trachomatis</it>. Using multivariate analysis, women were significantly more likely to provide urine samples than men (aOR = 1.53, 95% CI 1.14-2.06) as were those who reported no condom use at last intercourse (aOR = 1.95, 95% CI 1.44-2.62). Prevalence of <it>C trachomatis </it>infection among those who were sexually experienced was 7.3% in men and 5.3% in women.</p> <p>Conclusions</p> <p>Population-based surveys that use probabilistic sampling are a feasible way to obtain population estimates of <it>C trachomatis </it>prevalence among young adults in Croatia, but it is challenging to obtain an adequate response rate. The prevalence of <it>C trachomatis </it>among young adults in Croatia found in this study was higher than that found in other European countries with similar survey response rates.</p

Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

Abstract Background Chromatin loops form a basic unit of interphase nuclear organization, with chromatin loop anchor points providing contacts between regulatory regions and promoters. However, the mutational landscape at these anchor points remains under-studied. Here, we describe the unusual patterns of somatic mutations and germline variation associated with loop anchor points and explore the underlying features influencing these patterns. Results Analyses of whole genome sequencing datasets reveal that anchor points are strongly depleted for single nucleotide variants (SNVs) in tumours. Despite low SNV rates in their genomic neighbourhood, anchor points emerge as sites of evolutionary innovation, showing enrichment for structural variant (SV) breakpoints and a peak of SNVs at focal CTCF sites within the anchor points. Both CTCF-bound and non-CTCF anchor points harbour an excess of SV breakpoints in multiple tumour types and are prone to double-strand breaks in cell lines. Common fragile sites, which are hotspots for genome instability, also show elevated numbers of intersecting loop anchor points. Recurrently disrupted anchor points are enriched for genes with functions in cell cycle transitions and regions associated with predisposition to cancer. We also discover a novel class of CTCF-bound anchor points which overlap meiotic recombination hotspots and are enriched for the core PRDM9 binding motif, suggesting that the anchor points have been foci for diversity generated during recent human evolution. Conclusions We suggest that the unusual chromatin environment at loop anchor points underlies the elevated rates of variation observed, marking them as sites of regulatory importance but also genomic fragility

Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis.

Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis