Playing TET

Methylation of the fifth carbon of cytosine was the first epigenetic modification to be discovered in DNA. Recently, three new DNA modifications have come to light: hydroxymethylcytosine, formylcytosine, and carboxylcytosine, all generated by oxidation of methylcytosine by Ten Eleven Translocation (TET) enzymes. These modifications can initiate full DNA demethylation, but they are also likely to participate, like methylcytosine, in epigenetic signalling per se. A scenario is emerging in which coordinated regulation at multiple levels governs the participation of TETs in a wide range of physiological functions, sometimes via a mechanism unrelated to their enzymatic activity. Although still under construction, a sophisticated picture is rapidly forming where, according to the function to be performed, TETs ensure epigenetic marking to create specific landscapes, and whose improper build-up can lead to diseases such as cancer and neurodegenerative disorders. © 2014 The Authors.SCOPUS: re.jFLWINinfo:eu-repo/semantics/publishe

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

Rencontres Henri-Jean Martin : faire vivre la documentation régionale

Depuis 8 ans, les rencontres Henri-Jean Martin proposent un lieu de rencontre et d\u27échange pour les bibliothécaires travaillant dans des fonds patrimoniaux de toutes sortes. En quelques mots, voici leurs objectifs : offrir la possibilité de discuter des sujets les plus complexes en échangeant les expériences et en invitant des experts, rencontrer ses collègues, en toute liberté de parole et de débat. En 2014, les échanges portent sur la documentation régionale. La réflexion sur ce sujet riche, vaste et composite prend appui sur quatre pivots : les modalités de constitution spécifiques des fonds locaux ; les enjeux liés à la mémoire locale ; la définition mouvante du local dans les contextes urbains et numériques d’aujourd’hui, et l’enjeu politique de ces fonds quand ils s’inscrivent dans un projet de portée tout à la fois locale et universelle

Chemical intervention in plant sugar signalling increases yield and resilience

The pressing global issue of food insecurity due to population growth, diminishing land and variable climate can only be addressed in agriculture by improving both maximum crop yield potential and resilience. Genetic modification is one potential solution, but has yet to achieve worldwide acceptance, particularly for crops such as wheat. Trehalose-6-phosphate (T6P), a central sugar signal in plants, regulates sucrose use and allocation, underpinning crop growth and development. Here we show that application of a chemical intervention strategy directly modulates T6P levels in planta. Plant-permeable analogues of T6P were designed and constructed based on a ‘signalling-precursor’ concept for permeability, ready uptake and sunlight-triggered release of T6P in planta. We show that chemical intervention in a potent sugar signal increases grain yield, whereas application to vegetative tissue improves recovery and resurrection from drought. This technology offers a means to combine increases in yield with crop stress resilience. Given the generality of the T6P pathway in plants and other small-molecule signals in biology, these studies suggest that suitable synthetic exogenous small-molecule signal precursors can be used to directly enhance plant performance and perhaps other organism function

Autosomal and mitochondrial adaptation following admixture: a case study on the honeybees of Reunion Island.

The honeybee population of the tropical Reunion Island is a genetic admixture of the Apis mellifera unicolor subspecies, originally described in Madagascar, and of European subspecies, mainly A.m. carnica and A. m. ligustica, regularly imported to the island since the late 19th century. We took advantage of this population to study genetic admixing of the tropical-adapted indigenous and temperate-adapted European genetic backgrounds. Whole genome sequencing of 30 workers and 6 males from Reunion, compared to samples from Europe, Madagascar, Mauritius, Rodrigues and the Seychelles, revealed the Reunion honeybee population to be composed on average of 53.2 ± 5.9% A. m. unicolor nuclear genomic background, the rest being mainly composed of A. m. carnica and to a lesser extent A. m. ligustica. In striking contrast to this, only one out of the 36 honeybees from Reunion had a mitochondrial genome of European origin, suggesting selection has favoured the A. m. unicolor mitotype, which is possibly better adapted to the island's bioclimate. Local ancestry was determined along the chromosomes for all Reunion samples, and a test for preferential selection for the A. m. unicolor or European background revealed 15 regions significantly associated with the A. m. unicolor lineage and 9 regions with the European lineage. Our results provide insights into the long-term consequences of introducing exotic specimen on the nuclear and mitochondrial genomes of locally-adapted populations. (Résumé d'auteur

Detecting the impact of temperature on transmission of Zika, dengue, and chikungunya using mechanistic models

Recent epidemics of Zika, dengue, and chikungunya have heightened the need to understand the seasonal and geographic range of transmission by Aedes aegypti and Ae. albopictus mosquitoes. We use mechanistic transmission models to derive predictions for how the probability and magnitude of transmission for Zika, chikungunya, and dengue change with mean temperature, and we show that these predictions are well matched by human case data. Across all three viruses, models and human case data both show that transmission occurs between 18–34°C with maximal transmission occurring in a range from 26–29°C. Controlling for population size and two socioeconomic factors, temperature-dependent transmission based on our mechanistic model is an important predictor of human transmission occurrence and incidence. Risk maps indicate that tropical and subtropical regions are suitable for extended seasonal or year-round transmission, but transmission in temperate areas is limited to at most three months per year even if vectors are present. Such brief transmission windows limit the likelihood of major epidemics following disease introduction in temperate zones

Discovery of new modes of action of TET methyldioxygenases

It has been known for a long time that the cytosine base can be modified to produce a new nucleotide, identified as 5-methylcytosine (mC). In normal cells, mC is correctly distributed into the genome, but in many diseases including life-threatening cancers, its pattern is profoundly perturbed. In 2009, Anjana Rao, published that certain proteins, known as the TET enzymes, are capable of removing mC by further oxidizing it to 5-hydroxymethylcytosine (hmC). This original article, cited more than 1200 times, has led to a great expansion in our understanding of DNA methylation. Such recent publications expanded this knowledge by showing that the TETs successively oxidize hmC to 5-formylcytosine (fC) and 5-carboxylcytosine (caC). These oxidized methylcytosines have been implicated in several mechanisms of DNA demethylation, including “active” demethylation through base excision repair, and “passive” demethylation via successive rounds of DNA replication. In addition, DNA hydroxymethylation is thought to be involved in a wide range of diseases, and a marked decrease of hmC seems to be a “hallmark” of many cancers. However, little is known about the regulation of their modes of action. It is tempting to speculate that these proteins interact with a plethora of factors to elicit coordinated biological functions. Likewise, they might be regulated by environment, which in certain situations, could alter the hydroxymethylome landscape, and lead to cellular malfunction and diseases.In the first study, we pursued a large, unbiased screen of the TET interactome, and discovered that TET2 and TET3 interact with the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). OGT is a glycosyltransferase that adds N-acetylglucose moieties on various proteins, including histone H2B, expanding therefore the “histone code”. We further discovered that the TET-OGT association seems to enhance OGT activity and to potentiate glycosylation and stabilization of SET1/COMPASS, a complex that is responsible for the global deposition of the H3K4me3 histone mark that “decorates” active promoters. Finally, we could confirm a decreased genome-wide H3K4me3 deposition in a model of acute myeloid leukemia mutated for TET2, suggesting that the TET-OGT link is implicated in Health and Disease.In the second study, we looked at the impact of the environment on TET activity and on cellular hydroxymethylomes. We focused on oxidative stress assaults that are known to be involved in inflammation, a mediator of cancer and neurodegenerative diseases. We observed a significant decrease of hmC in cell lines treated with various oxidant stressors, likely due to a direct inactivation of the TETs catalytic domain. Moreover, gene ontology analysis of differentially hydroxymethylated regions (dhMRs), profiled by deep-sequencing on treated vs non-treated cells, highlighted pathways involved in oxidative stress response. The implication of TETs in oxidative stress response was further emphasized by a decreased proliferation of TET1-depleted cells when they are treated with oxidant stressors. Importantly, those results were confirmed in mice knockout for the major antioxidant enzymes GPx1 and GPx2. In conclusion, the work of this thesis contributed to better understand the modes of action of the TET proteins, through (1) direct interaction with OGT, and (2) via direct regulation by oxidative-stress-associated molecules, and we hope that these results will bring new insights to better understand these fascinating enzymes. Doctorat en Sciences biomédicales et pharmaceutiquesinfo:eu-repo/semantics/nonPublishe

The expanding world of mRNA modifications: Expanding the RNA alphabet

Our understanding of the post-transcriptional modifications that decorate mRNAs, a regulatory layer positioned between DNA and proteins, is in its infancy. Recent advances in genome-wide mapping of pseudouridine (ψ), N6-methyladenosine (m6A), 5-methylcytosine (5mrC), its oxidation product 5-hydroxymethylcytosine (5hmrC), and N1-methyladenosine (m1A) have proven that these modifications unsuspectedly occur from dozens to thousands of different gene transcripts in eukaryotic cells. Therefore epigenetics cannot only be restricted to chromatin modifications, and, when studying gene regulation, one has to consider the expanding kingdom of RNA modifications, also known as the epitranscriptome.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

TET proteins: On the frenetic hunt for new cytosine modifications

Epigenetic genome marking and chromatin regulation are central to establishing tissue-specific gene expression programs, and hence to several biological processes. Until recently, the only known epigenetic mark on DNA in mammals was 5-methylcytosine, established and propagated by DNA methyltransferases and generally associated with gene repression. All of a sudden, a host of new actorsc-novel cytosine modifications and the ten eleven translocation (TET) enzymesc-has appeared on the scene, sparking great interest. The challenge is now to uncover the roles they play and how they relate to DNA demethylation. Knowledge is accumulating at a frantic pace, linking these new players to essential biological processes (e.g. cell pluripotency and development) and also to cancerogenesis. Here, we review the recent progress in this exciting field, highlighting the TET enzymes as epigenetic DNA modifiers, their physiological roles, and their functions in health and disease.We also discuss the need to find relevant TET interactants and the newly discovered TETO-linked N-acetylglucosamine transferase (OGT) pathway ©The Author 2013. Published by Oxford University Press.SCOPUS: ar.jinfo:eu-repo/semantics/publishe