H3K18 lactylation marks tissue‑specific active enhancers

Background: Histone lactylation has been recently described as a novel histone posttranslational modification linking cellular metabolism to epigenetic regulation. Results: Given the expected relevance of this modification and current limited knowledge of its function, we generate genome-wide datasets of H3K18la distribution in various in vitro and in vivo samples, including mouse embryonic stem cells, macrophages, adipocytes, and mouse and human skeletal muscle. We compare them to profiles of well-established histone modifications and gene expression patterns. Supervised and unsupervised bioinformatics analysis shows that global H3K18la distribution resembles H3K27ac, although we also find notable differences. H3K18la marks active CpG islandcontaining promoters of highly expressed genes across most tissues assessed, including many housekeeping genes, and positively correlates with H3K27ac and H3K4me3 as well as with gene expression. In addition, H3K18la is enriched at active enhancers that lie in proximity to genes that are functionally important for the respective tissue. Conclusions: Overall, our data suggests that H3K18la is not only a marker for active promoters, but also a mark of tissue specific active enhancers.ETH Zurich ETH Zurich core fundingEuropean Research Council (ERC) European Commission 803491Botnar Research Centre for Child Health Multi-Investigator ProjectWorld Food System Center of ETH ZurichIntegrative Food and Nutrition Center of EPF

Planetare Gesundheit – transformative Lehr- und Lernformate zur Klima- und Nachhaltigkeitskrise für Gesundheitsberufe

Funder: Ludwig-Maximilians-Universität München (1024)Zusammenfassung: Die Dringlichkeit der Klima- und Nachhaltigkeitskrise und ihre Auswirkungen auf die menschliche Gesundheit rücken auch im deutschen Gesundheitswesen zunehmend in den Fokus. Um ein weiteres Fortschreiten der Klima- und Nachhaltigkeitskrise zu verhindern, sind tiefgreifende Transformationsprozesse in allen gesellschaftlichen Sektoren notwendig (z. B. Verkehr, Energieerzeugung, Ernährungssystem). Angehörige der Gesundheitsberufe haben auf Basis ihrer ethischen Verpflichtung des Nichtschadens und ihrer guten Vertrauenswerte in der Gesellschaft das Potenzial, einen wichtigen Beitrag zu den notwendigen Transformationsprozessen zu leisten. Damit sie dieses Potenzial zur Gänze ausschöpfen können, sollten Angehörige der Gesundheitsberufe im Rahmen ihrer Aus‑, Fort- und Weiterbildung bei der Entwicklung von Kompetenzen begleitet werden, die zu transformativem Handeln befähigen. Wir führen in diesem Artikel in das Konzept der planetaren Gesundheit ein, das hierfür sowohl inhaltliche als auch ethische Orientierung gibt. Außerdem geben wir einen Überblick über aktuelle Lehr- und Lernformate und identifizieren Aspekte, die zur Weiterentwicklung der Lehre im Bereich planetare Gesundheit beitragen könnten

Planetare Gesundheit – transformative Lehr- und Lernformate zur Klima- und Nachhaltigkeitskrise für Gesundheitsberufe

Funder: Ludwig-Maximilians-Universität München (1024)Zusammenfassung: Die Dringlichkeit der Klima- und Nachhaltigkeitskrise und ihre Auswirkungen auf die menschliche Gesundheit rücken auch im deutschen Gesundheitswesen zunehmend in den Fokus. Um ein weiteres Fortschreiten der Klima- und Nachhaltigkeitskrise zu verhindern, sind tiefgreifende Transformationsprozesse in allen gesellschaftlichen Sektoren notwendig (z. B. Verkehr, Energieerzeugung, Ernährungssystem). Angehörige der Gesundheitsberufe haben auf Basis ihrer ethischen Verpflichtung des Nichtschadens und ihrer guten Vertrauenswerte in der Gesellschaft das Potenzial, einen wichtigen Beitrag zu den notwendigen Transformationsprozessen zu leisten. Damit sie dieses Potenzial zur Gänze ausschöpfen können, sollten Angehörige der Gesundheitsberufe im Rahmen ihrer Aus‑, Fort- und Weiterbildung bei der Entwicklung von Kompetenzen begleitet werden, die zu transformativem Handeln befähigen. Wir führen in diesem Artikel in das Konzept der planetaren Gesundheit ein, das hierfür sowohl inhaltliche als auch ethische Orientierung gibt. Außerdem geben wir einen Überblick über aktuelle Lehr- und Lernformate und identifizieren Aspekte, die zur Weiterentwicklung der Lehre im Bereich planetare Gesundheit beitragen könnten

H3K18 lactylation marks tissue-specific active enhancers

Background: Histone lactylation has been recently described as a novel histone post-translational modification linking cellular metabolism to epigenetic regulation. Results: Given the expected relevance of this modification and current limited knowledge of its function, we generate genome-wide datasets of H3K18la distribution in various in vitro and in vivo samples, including mouse embryonic stem cells, macrophages, adipocytes, and mouse and human skeletal muscle. We compare them to profiles of well-established histone modifications and gene expression patterns. Supervised and unsupervised bioinformatics analysis shows that global H3K18la distribution resembles H3K27ac, although we also find notable differences. H3K18la marks active CpG island-containing promoters of highly expressed genes across most tissues assessed, including many housekeeping genes, and positively correlates with H3K27ac and H3K4me3 as well as with gene expression. In addition, H3K18la is enriched at active enhancers that lie in proximity to genes that are functionally important for the respective tissue. Conclusions: Overall, our data suggests that H3K18la is not only a marker for active promoters, but also a mark of tissue specific active enhancers. Keywords: Adipocyte; CUT&Tag; ChromHMM; Embryonic stem cell; Enhancer; Epigenetics; H3K18la; Histone post-translational modification; Lactate; Lactylation; Macrophage; Muscle; Promoter

Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers.

PURPOSE: CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. PATIENTS AND METHODS: CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. RESULTS: Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. CONCLUSION: These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.NIH

Genome-wide association study of germline variants and breast cancer-specific mortality.

BackgroundWe examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.MethodsMeta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).ResultsWe did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.ConclusionsWe uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients

Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90–0.94; P = 8.96 × 10−15)) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10−09, r2 = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10−11, r2 = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus

ARTEFACTS: How do we want to deal with the future of our one and only planet?

The European Commission’s Science and Knowledge Service, the Joint Research Centre (JRC), decided to try working hand-in-hand with leading European science centres and museums. Behind this decision was the idea that the JRC could better support EU Institutions in engaging with the European public. The fact that European Union policies are firmly based on scientific evidence is a strong message which the JRC is uniquely able to illustrate. Such a collaboration would not only provide a platform to explain the benefits of EU policies to our daily lives but also provide an opportunity for European citizens to engage by taking a more active part in the EU policy making process for the future. A PILOT PROGRAMME To test the idea, the JRC launched an experimental programme to work with science museums: a perfect partner for three compelling reasons. Firstly, they attract a large and growing number of visitors. Leading science museums in Europe have typically 500 000 visitors per year. Furthermore, they are based in large European cities and attract local visitors as well as tourists from across Europe and beyond. The second reason for working with museums is that they have mastered the art of how to communicate key elements of sophisticated arguments across to the public and making complex topics of public interest readily accessible. That is a high-value added skill and a crucial part of the valorisation of public-funded research, never to be underestimated. Finally museums are, at present, undergoing something of a renaissance. Museums today are vibrant environments offering new techniques and technologies to both inform and entertain, and attract visitors of all demographics.JRC.H.2-Knowledge Management Methodologies, Communities and Disseminatio

Genome-wide association study of germline variants and breast cancer-specific mortality

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10

TET enzymes as oxygen-dependent tumor suppressors: exciting new avenues for cancer management

status: publishe