TIP55, a splice isoform of the KAT5 acetyltransferase, is essential for developmental gene regulation and organogenesis

Regulation of chromatin structure is critical for cell type-specific gene expression. Many chromatin regulatory complexes exist in several different forms, due to alternative splicing and differential incorporation of accessory subunits. However, in vivo studies often utilize mutations that eliminate multiple forms of complexes, preventing assessment of the specific roles of each. Here we examined the developmental roles of the TIP55 isoform of the KAT5 histone acetyltransferase. In contrast to the pre-implantation lethal phenotype of mice lacking all four Kat5 transcripts, mice specifically deficient for Tip55 die around embryonic day 11.5 (E11.5). Prior to developmental arrest, defects in heart and neural tube were evident in Tip55 mutant embryos. Specification of cardiac and neural cell fates appeared normal in Tip55 mutants. However, cell division and survival were impaired in heart and neural tube, respectively, revealing a role for TIP55 in cellular proliferation. Consistent with these findings, transcriptome profiling revealed perturbations in genes that function in multiple cell types and developmental pathways. These findings show that Tip55 is dispensable for the pre- and early post-implantation roles of Kat5, but is essential during organogenesis. Our results raise the possibility that isoform-specific functions of other chromatin regulatory proteins may play important roles in development

Prevalence of Nutrition and Health-Related Claims on Pre-Packaged Foods: A Five-Country Study in Europe

This study is part of the research undertaken in the EU funded project CLYMBOL (“Role of health-related CLaims and sYMBOLs in consumer behaviour”). The first phase of this project consisted of mapping the prevalence of symbolic and non-symbolic nutrition and health-related claims (NHC) on foods and non-alcoholic beverages in five European countries. Pre-packaged foods and drinks were sampled based on a standardized sampling protocol, using store lists or a store floor plan. Data collection took place across five countries, in three types of stores. A total of 2034 foods and drinks were sampled and packaging information was analyzed. At least one claim was identified for 26% (95% CI (24.0%–27.9%)) of all foods and drinks sampled. Six percent of these claims were symbolic. The majority of the claims were nutrition claims (64%), followed by health claims (29%) and health-related ingredient claims (6%). The most common health claims were nutrient and other function claims (47% of all claims), followed by disease risk reduction claims (5%). Eight percent of the health claims were children’s development and health claims but these were only observed on less than 1% (0.4%–1.1%) of the foods. The category of foods for specific dietary use had the highest proportion of NHC (70% of foods carried a claim). The prevalence of symbolic and non-symbolic NHC varies across European countries and between different food categories. This study provides baseline data for policy makers and the food industry to monitor and evaluate the use of claims on food packaging

Elevated levels of TRF2 induce telomeric ultrafine anaphase bridges and rapid telomere deletions.

The shelterin protein TRF2 is essential for chromosome-end protection. Depletion of TRF2 causes chromosome end-to-end fusions, initiating genomic instability that can be cancer promoting. Paradoxically, significant increased levels of TRF2 are observed in a subset of human cancers. Experimental overexpression of TRF2 has also been shown to induce telomere shortening, through an unknown mechanism. Here we report that TRF2 overexpression results in replication stalling in duplex telomeric repeat tracts and the subsequent formation of telomeric ultrafine anaphase bridges (UFBs), ultimately leading to stochastic loss of telomeric sequences. These TRF2 overexpression-induced telomere deletions generate chromosome fusions resembling those detected in human cancers and in mammalian cells containing critically shortened telomeres. Therefore, our findings have uncovered a second pathway by which altered TRF2 protein levels can induce end-to-end fusions. The observations also provide mechanistic insight into the molecular basis of genomic instability in tumour cells containing significantly increased TRF2 levels

Elevated levels of TRF2 induce telomeric ultrafine anaphase bridges and rapid telomere deletions.

The shelterin protein TRF2 is essential for chromosome-end protection. Depletion of TRF2 causes chromosome end-to-end fusions, initiating genomic instability that can be cancer promoting. Paradoxically, significant increased levels of TRF2 are observed in a subset of human cancers. Experimental overexpression of TRF2 has also been shown to induce telomere shortening, through an unknown mechanism. Here we report that TRF2 overexpression results in replication stalling in duplex telomeric repeat tracts and the subsequent formation of telomeric ultrafine anaphase bridges (UFBs), ultimately leading to stochastic loss of telomeric sequences. These TRF2 overexpression-induced telomere deletions generate chromosome fusions resembling those detected in human cancers and in mammalian cells containing critically shortened telomeres. Therefore, our findings have uncovered a second pathway by which altered TRF2 protein levels can induce end-to-end fusions. The observations also provide mechanistic insight into the molecular basis of genomic instability in tumour cells containing significantly increased TRF2 levels

Both the classical and alternative non-homologous end joining pathways contribute to the fusion of drastically shortened telomeres induced by TRF2 overexpression

The double-stranded telomeric binding protein TRF2 is expressed in many human cancers at elevated levels. Moreover, experimental overexpression of TRF2 in human cells causes replication stalling in telomeric tracts, which leads to drastic telomere shortening and fusion of deprotected chromosome ends. To understand which end joining pathway is involved in mediating these chromosome fusions, we overexpressed TRF2 in human HCT116 cell lines that were deficient for the DNA Ligase 4 (Lig4)-dependent classical non-homologous end joining (C-NHEJ) or the DNA Ligase 3 (Lig3)-dependent alternative non-homologous end joining (A-NHEJ) pathway. Surprisingly, abrogation of either Lig4 or nuclear Lig3 significantly reduced inter-chromosomal fusion of drastically shortened telomeres, suggesting that both the C-NHEJ and A-NHEJ pathways are involved in mediating this type of fusion. Fusion between deprotected sister chromatids, however, only required the Lig3-dependent A-NHEJ pathway. Interestingly, a previous study reported similar end joining pathway requirements for the fusion of critically shortened telomeres during a telomere attrition-based cellular crisis. We speculate that, as in cellular crisis, the same repair pathway(s) may drive clonal and genomic evolution in human cancers containing elevated TRF2 levels

Country Differences in the History of Use of Health Claims and Symbols

Health-related claims and symbols are intended as aids to help consumers make informed and healthier food choices but they can also stimulate the food industry to develop food that goes hand in hand with a healthier lifestyle. In order to better understand the role that health claims and symbols currently have and in the future potentially can have, the objective of the CLYMBOL project (“Role of health-related claims and symbols in consumer behaviour”, Grant no 311963) is to investigate consumers’ understanding of health claims and symbols, and how they affect purchasing and consumption [1].As part of this endeavour, it is important to understand the history of use of claims and symbols in Europe. What have consumers been exposed to and how were these health-related messages used and discussed among the public? In this study, we interviewed key stakeholders across Europe about how health claims have been regulated in their country, how health symbols have been and currently are being treated, what form of monitoring there is or should be and how both health claims and symbols have been debated in the public opinion. In 26 European Union (EU) Member States, opinions from 53 key informants from up to three different stakeholder groups were gathered: national food authorities, representatives of the food industry, and consumer organisations.While 14 Member States reported (at least partial) regulation of the use of health claims and/or symbols before the introduction of the EU Regulation (EC 1924/2006) on nutrition and health claims made on foods [2], mandatory reporting of use had only been in place in three EU Member States. A number of voluntary codes of practice for health claims and/or symbols (i.e. pre-approval or justification when challenged) was said to be in use in 15 Member States. There are only a few national databases on health claims and symbols available, the data for which is often incomplete. Only eight Member States reported having some form of database from which information about health claims and symbols could be extracted. The stakeholders interviewed expressed a strong interest in measuring the impact of health claims and symbols, particularly research into the effects on consumer behaviour (e.g. awareness and understanding, attitudes towards products carrying claims and symbols and purchase/consumption effects), public health (health outcomes and changes in national health status due to the introduction of claims and symbols on food products) and economic aspects including sales, return on investment and reputation measurements. Public debates were said to have evolved around the topics of consumer understanding of claims, acceptance as well as trust in the information presented but also the effects on vulnerable groups such as children and elderly consumers. Another field of debate was said to have been the question of the effectiveness of health claims and symbols. Lastly, stakeholders reported that public debates focussed mainly on the legislative aspects, i.e. how to apply the EU Regulation (No 1924/2006) with regards to wording issues, the evaluation process at the European Food Safety Authority (EFSA), the status of various claims and the nutrient profile modelling to be introduced in Europe.<br/