A conceptual model of suicide in rural areas

Context: Suicide is an important public health issue among rural communities although there is no single pattern of suicide in rural areas. Despite this, there are common themes in much of the research evidence on suicide in rural areas. From the published research in the area, a conceptual model of rural suicide has been developed which can be used by clinical and public health services when considering possible routes of intervention.Issue: A conceptual model can be defined as 'a type of diagram which shows a set of relationships between factors that are believed to impact or lead to a target condition'. The model presented here uses the 'Cry of pain/ Entrapment' model of suicide risk to build a framework of factors which are associated with suicide in rural areas. Cross-setting factors associated with suicide rates include gender, poverty, mental illness, substance use, biological factors including apparent genetic risk, coping skills and media coverage of suicide. There are, however, other factors that appear to have particular importance in rural areas. These include rural stressors, such as isolation and political and social exclusion; factors affecting support, including social support, cultural norms on help-seeking, stigma associated with mental illness service availability; factors affecting the decision to self-harm, including modelling and cultural views on self-harm, and issues affecting the likelihood of self-harm resulting in death, including method availability, norms on methods of self-harm and treatment availability after harm occurs. Identifying which of these areas are the greatest local priorities helps to target activity.Lessons learned: This model provides a way of considering suicide in rural areas. Local staff can use it to consider which issues are most relevant to their area. It allows classification of existing interventions, and deciding which other areas of work might be of local value. For researchers and service planners, it provides a way of classifying interventions and describing projects

BayesPeak: Bayesian analysis of ChIP-seq data.

BACKGROUND: High-throughput sequencing technology has become popular and widely used to study protein and DNA interactions. Chromatin immunoprecipitation, followed by sequencing of the resulting samples, produces large amounts of data that can be used to map genomic features such as transcription factor binding sites and histone modifications. METHODS: Our proposed statistical algorithm, BayesPeak, uses a fully Bayesian hidden Markov model to detect enriched locations in the genome. The structure accommodates the natural features of the Solexa/Illumina sequencing data and allows for overdispersion in the abundance of reads in different regions. Moreover, a control sample can be incorporated in the analysis to account for experimental and sequence biases. Markov chain Monte Carlo algorithms are applied to estimate the posterior distributions of the model parameters, and posterior probabilities are used to detect the sites of interest. CONCLUSION: We have presented a flexible approach for identifying peaks from ChIP-seq reads, suitable for use on both transcription factor binding and histone modification data. Our method estimates probabilities of enrichment that can be used in downstream analysis. The method is assessed using experimentally verified data and is shown to provide high-confidence calls with low false positive rates.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Latent regulatory potential of human-specific repetitive elements

At least half of the human genome is derived from repetitive elements, which are often lineage specific and silenced by a variety of genetic and epigenetic mechanisms. Using a transchromosomic mouse strain that transmits an almost complete single copy of human chromosome 21 via the female germline, we show that a heterologous regulatory environment can transcriptionally activate transposon-derived human regulatory regions. In the mouse nucleus, hundreds of locations on human chromosome 21 newly associate with activating histone modifications in both somatic and germline tissues, and influence the gene expression of nearby transcripts. These regions are enriched with primate and human lineage-specific transposable elements, and their activation corresponds to changes in DNA methylation at CpG dinucleotides. This study reveals the latent regulatory potential of the repetitive human genome and illustrates the species specificity of mechanisms that control it

5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer

The authors would like to acknowledge the support of The University of Cambridge, Cancer Research UK (CRUK SEB-Institute Group Award A ref10182; CRUK Senior fellowship C10112/A11388 to AEKI) and Hutchison Whampoa Limited. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. FF is a ULB Professor funded by grants from the F.N.R.S. and Télévie, the IUAP P7/03 programme, the ARC (AUWB-2010-2015 ULB-No 7), the WB Health program and the Fonds Gaston Ithier. Data access: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jpwzvsowiyuamzs&acc=GSE47592Background : The discovery of cytosine hydroxymethylation (5hmC) as a mechanism that potentially controls DNA methylation changes typical of neoplasia prompted us to investigate its behaviour in colon cancer. 5hmC is globally reduced in proliferating cells such as colon tumours and the gut crypt progenitors, from which tumours can arise. Results : Here, we show that colorectal tumours and cancer cells express Ten-Eleven-Translocation (TET) transcripts at levels similar to normal tissues. Genome-wide analyses show that promoters marked by 5hmC in normal tissue, and those identified as TET2 targets in colorectal cancer cells, are resistant to methylation gain in cancer. In vitro studies of TET2 in cancer cells confirm that these promoters are resistant to methylation gain independently of sustained TET2 expression. We also find that a considerable number of the methylation gain-resistant promoters marked by 5hmC in normal colon overlap with those that are marked with poised bivalent histone modifications in embryonic stem cells. Conclusions : Together our results indicate that promoters that acquire 5hmC upon normal colon differentiation are innately resistant to neoplastic hypermethylation by mechanisms that do not require high levels of 5hmC in tumours. Our study highlights the potential of cytosine modifications as biomarkers of cancerous cell proliferation.Publisher PDFPeer reviewe

Progesterone receptor modulates ERα action in breast cancer.

Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist ligands, PR associates with ERα to direct ERα chromatin binding events within breast cancer cells, resulting in a unique gene expression programme that is associated with good clinical outcome. Progesterone inhibited oestrogen-mediated growth of ERα(+) cell line xenografts and primary ERα(+) breast tumour explants, and had increased anti-proliferative effects when coupled with an ERα antagonist. Copy number loss of PGR, the gene coding for PR, is a common feature in ERα(+) breast cancers, explaining lower PR levels in a subset of cases. Our findings indicate that PR functions as a molecular rheostat to control ERα chromatin binding and transcriptional activity, which has important implications for prognosis and therapeutic interventions.We would like to acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. Research reported in this manuscript was supported by the National Cancer Institute of the National Institutes of Health under award number 5P30CA142543 (to UT Southwestern) and Department of Defense grants W81XWH-12-1-0288-03 (GVR). W.D.T. is supported by grants from the National Health and Medical Research Council of Australia (ID 1008349; ID 1084416) and Cancer Australia (ID 627229) T.E.H held a Fellowship Award from the US Department of Defense Breast Cancer Research Program (BCRP; #W81XWH-11-1-0592) and currently is supported by a Florey Fellowship from the Royal Adelaide Hospital Research Foundation. J.S.C is supported by an ERC starting grant and an EMBO Young investigator award.This is the accepted manuscript. The final version is available at www.nature.com/nature/journal/v523/n7560/full/nature14583.htm

Genome-Scale Validation of Deep-Sequencing Libraries

Chromatin immunoprecipitation followed by high-throughput (HTP) sequencing (ChIP-seq) is a powerful tool to establish protein-DNA interactions genome-wide. The primary limitation of its broad application at present is the often-limited access to sequencers. Here we report a protocol, Mab-seq, that generates genome-scale quality evaluations for nucleic acid libraries intended for deep-sequencing. We show how commercially available genomic microarrays can be used to maximize the efficiency of library creation and quickly generate reliable preliminary data on a chromosomal scale in advance of deep sequencing. We also exploit this technique to compare enriched regions identified using microarrays with those identified by sequencing, demonstrating that they agree on a core set of clearly identified enriched regions, while characterizing the additional enriched regions identifiable using HTP sequencing

Independence of HIF1a and androgen signaling pathways in prostate cancer

Funder: Cancer Research UK; doi: http://dx.doi.org/10.13039/501100000289Abstract: Background: Therapeutic targeting of the androgen signaling pathway is a mainstay treatment for prostate cancer. Although initially effective, resistance to androgen targeted therapies develops followed by disease progression to castrate-resistant prostate cancer (CRPC). Hypoxia and HIF1a have been implicated in the development of resistance to androgen targeted therapies and progression to CRCP. The interplay between the androgen and hypoxia/HIF1a signaling axes was investigated. Methods: In vitro stable expression of HIF1a was established in the LNCaP cell line by physiological induction or retroviral transduction. Tumor xenografts with stable expression of HIF1a were established in castrated and non-castrated mouse models. Gene expression analysis identified transcriptional changes in response to androgen treatment, hypoxia and HIF1a. The binding sites of the AR and HIF transcription factors were identified using ChIP-seq. Results: Androgen and HIF1a signaling promoted proliferation in vitro and enhanced tumor growth in vivo. The stable expression of HIF1a in vivo restored tumor growth in the absence of endogenous androgens. Hypoxia reduced AR binding sites whereas HIF binding sites were increased with androgen treatment under hypoxia. Gene expression analysis identified seven genes that were upregulated both by AR and HIF1a, of which six were prognostic. Conclusions: The oncogenic AR, hypoxia and HIF1a pathways support prostate cancer development through independent signaling pathways and transcriptomic profiles. AR and hypoxia/HIF1a signaling pathways independently promote prostate cancer progression and therapeutic targeting of both pathways simultaneously is warranted

Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.

Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer

Genomic correlates of glatiramer acetate adverse cardiovascular effects lead to a novel locus mediating coronary risk

Glatiramer acetate is used therapeutically in multiple sclerosis but also known for adverse effects including elevated coronary artery disease (CAD) risk. The mechanisms underlying the cardiovascular side effects of the medication are unclear. Here, we made use of the chromosomal variation in the genes that are known to be affected by glatiramer treatment. Focusing on genes and gene products reported by drug-gene interaction database to interact with glatiramer acetate we explored a large meta-analysis on CAD genome-wide association studies aiming firstly, to investigate whether variants in these genes also affect cardiovascular risk and secondly, to identify new CAD risk genes. We traced association signals in a 200-kb region around genomic positions of genes interacting with glatiramer in up to 60 801 CAD cases and 123 504 controls. We validated the identified association in additional 21 934 CAD cases and 76 087 controls. We identified three new CAD risk alleles within the TGFB1 region on chromosome 19 that independently affect CAD risk. The lead SNP rs12459996 was genome-wide significantly associated with CAD in the extended meta-analysis (odds ratio 1.09, p = 1.58×10-12). The other two SNPs at the locus were not in linkage disequilibrium with the lead SNP and by a conditional analysis showed p-values of 4.05 × 10-10 and 2.21 × 10-6. Thus, studying genes reported to interact with glatiramer acetate we identified genetic variants that concordantly with the drug increase the risk of CAD. Of these, TGFB1 displayed signal for association. Indeed, the gene has been associated with CAD previously in both in vivo and in vitro studies. Here we establish genome-wide significant association with CAD in large human samples.This work was supported by grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014 and SysInflame, grant 01ZX1306A), and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no HEALTH-F2-2013-601456 (CVgenes-at-target). Further grants were received from the DFG as part of the Sonderforschungsbereich CRC 1123 (B2). T.K. was supported by a DZHK Rotation Grant. I.B. was supported by the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’. F.W.A. is supported by a Dekker scholarship-Junior Staff Member 2014T001 - Netherlands Heart Foundation and UCL Hospitals NIHR Biomedical Research Centre