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

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

What are the barriers towards cervical cancer screening for vulnerable women? A qualitative comparative analysis of stakeholder perspectives in seven European countries

Objectives The aim of this study was to map and compare stakeholders’ perceptions of barriers towards cervical cancer screening for vulnerable women in seven European countries. Design In Collaborative User Boards, stakeholders were invited to participate to identify barriers towards participation in cervical cancer screening. Setting The study is nested in the European Union-funded project CBIG-SCREEN which aims to tackle inequity in cervical cancer screening for vulnerable women (www.cbig-screen.eu). Data collection took place in Bulgaria, Denmark, Estonia, France, Italy, Portugal and Romania. Participants Participants represented micro-level stakeholders covering representatives of users, that is, vulnerable women, meso-level stakeholders covering healthcare professionals and social workers, and macro-level stakeholders covering programme managers and decision-makers. Methods Across the seven countries, 25 meetings in Collaborative User Boards with a duration of 2 hours took place between October 2021 and June 2022. The meetings were video recorded or audio recorded, transcribed and translated into English for a qualitative framework analysis. Results 120 participants took part in the Collaborative User Boards. Context-specific barriers were related to different healthcare systems and characteristics of vulnerable populations. In Romania and Bulgaria, the lack of a continuous screening effort and lack of ways to identify eligible women were identified as barriers for all women rather than being specific for women in vulnerable situations. The participants in Denmark, Estonia, France, Italy and Portugal identified providers’ lack of cultural and social sensitivity towards vulnerable women as barriers. In all countries, vulnerable women’s fear, shame and lack of priority to preventive healthcare were identified as psychological barriers. Conclusion The study provides an overview of stakeholders’ perceived barriers towards vulnerable women’s cervical cancer screening participation in seven European countries. The organisation of healthcare systems and the maturity of screening programmes differ between countries, while vulnerable women’s psychological barriers had several similarities.The study is part of the CBIG-SCREEN, an EU-funded 5-year project under the EU Horizon 2020 Research and Innovation Programme (Grant Agreement No 964049)

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

Work environments and HIV prevention: a qualitative review and meta-synthesis of sex worker narratives

BACKGROUND: Sex workers (SWs) experience a disproportionately high burden of HIV, with evidence indicating that complex and dynamic factors within work environments play a critical role in mitigating or producing HIV risks in sex work. In light of sweeping policy efforts to further criminalize sex work globally, coupled with emerging calls for structural responses situated in labour and human-rights frameworks, this meta-synthesis of the qualitative and ethnographic literature sought to examine SWs’ narratives to elucidate the ways in which physical, social and policy features of diverse work environments influence SWs’ agency to engage in HIV prevention. METHODS: We conducted a meta-synthesis of qualitative and ethnographic studies published from 2008 to 2014 to elucidate SWs’ narratives and lived experiences of the complex and nuanced ways in which physical, social, and policy features of indoor and outdoor work environments shape HIV prevention in the sex industry. RESULTS: Twenty-four qualitative and/or ethnographic studies were included in this meta-synthesis. SWs’ narratives revealed the nuanced ways that physical, social, and policy features of work environments shaped HIV risk and interacted with macrostructural constraints (e.g., criminalization, stigma) and community determinants (e.g., sex worker empowerment initiatives) to shape SWs’ agency in negotiating condom use. SWs’ narratives revealed the ways in which the existence of occupational health and safety standards in indoor establishments, as well as protective practices of third parties (e.g., condom promotion) and other SWs/peers were critical ways of enhancing safety and sexual risk negotiation within indoor work environments. Additionally, working in settings where negative interactions with law enforcement were minimized (e.g., working in decriminalized contexts or environments in which peers/managers successfully deterred unjust policing practices) was critical for supporting SWs’ agency to negotiate HIV prevention. CONCLUSIONS: Policy reforms to remove punitive approaches to sex work, ensure supportive workplace standards and policies, and foster SWs’ ability to work collectively are recommended to foster the realization of SWs’ health and human rights across diverse settings. Future qualitative and mixed-methods research is recommended to ensure that HIV policies and programmes are grounded in SWs’ voices and realities, particularly in more under-represented regions such as Eastern Europe and Sub-Saharan Africa. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12889-015-2491-x) contains supplementary material, which is available to authorized users

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

Chlamydia prevalence in the general population: is there a sex difference? A systematic review.

Contains fulltext : 125531.pdf (publisher's version ) (Open Access

Self-reported activity limitations among the population aged 20–79 in Estonia: a cross-sectional study

Background: Along with population ageing, limitations in activities of daily living constitute a rising health-related burden in demographically advanced countries. The present study aims to assess the prevalence of self-reported activity limitations derived from chronic conditions and social variation of limitations in the subgroups of the population aged 20–79 years in Estonia. Methods: A cross-sectional study employs data from the second round of the Estonian Family and Fertility Survey, a national project in the framework of Gender and Generation Programme. The target population covers age groups of 20–79 years. A nationally representative probability sample was drawn from the 2000 population census. Face-to-face interviews (n = 7855) were conducted in 2004–05. Results: The estimated prevalence of activity limitations with chronic conditions is 18.5% (95% CI 17.6–19.4) and the prevalence of severe limitations is 10.6% (95% CI 9.9–11.3) among the population. The logistic regression model shows significant differences in activity limitations associated with age, educational attainment and marital status. Conclusions: Judging from our results and the EU structural indicators on health, the prevalence of activity limitations derived from chronic conditions is comparatively high in Estonia. The measures to prevent activity limitations and disability should receive a higher priority in Estonia