Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation

Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. Theseinteractions takeplace in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance.Institut National du Cancer (INCa, France, in part); European Commission (EC) Seventh Framework Programme (FP7) Translational Cancer Research (TRANSCAN) Framework; Fondation ARC pour la Recherche sur le Cancer (France) (to Z.H.); Fonds National de la Recherche, Luxembourg [10100060 to A.S.]; IARC Fellowship (Marie Curie actions – People – COFUND to N.F.J., in part); PoSTDoctoral Fellowship of the Basque Government; Swiss National Science Foundation (SNSF) (to L.V., V.Y., R.M.). Funding for open access charge: IARC regular budge

Temporal trends of population viral suppression in the context of Universal Test and Treat: the ANRS 12249 TasP trial in rural South Africa

Introduction: The universal test-and-treat (UTT) strategy aims to maximize population viral suppression (PVS), that is, the proportion of all people living with HIV (PLHIV) on antiretroviral treatment (ART) and virally suppressed, with the goal of reducing HIV transmission at the population level. This article explores the extent to which temporal changes in PVS explain the observed lack of association between universal treatment and cumulative HIV incidence seen in the ANRS 12249 TasP trial conducted in rural South Africa. Methods: The TasP cluster-randomized trial (2012 to 2016) implemented six-monthly repeat home-based HIV counselling and testing (RHBCT) and referral of PLHIV to local HIV clinics in 2 9 11 clusters opened sequentially. ART was initiated according to national guidelines in control clusters and regardless of CD4 count in intervention clusters. We measured residency status, HIV status, and HIV care status for each participant on a daily basis. PVS was computed per cluster among all resident PLHIV (≥16, including those not in care) at cluster opening and daily thereafter. We used a mixed linear model to explore time patterns in PVS, adjusting for sociodemographic changes at the cluster level. Results: 8563 PLHIV were followed. During the course of the trial, PVS increased significantly in both arms (23.5% to 46.2% in intervention, +22.8, p < 0.001; 26.0% to 44.6% in control, +18.6, p < 0.001). That increase was similar in both arms (p = 0.514). In the final adjusted model, PVS increase was most associated with increased RHBCT and the implementation of local trial clinics (measured by time since cluster opening). Contextual changes (measured by calendar time) also contributed slightly. The effect of universal ART (trial arm) was positive but limited. Conclusions: PVS was improved significantly but similarly in both trial arms, explaining partly the null effect observed in terms of cumulative HIV incidence between arms. The PVS gains due to changes in ART-initiation guidelines alone are relatively small compared to gains obtained by strategies to maximize testing and linkage to care. The achievement of the 90-90-90 targets will not be met if the operational and implementational challenges limiting access to care and treatment, often context-specific, are not properly addressed. Clinical trial number: NCT01509508 (clinicalTrials.gov)/DOH-27-0512-3974 (South African National Clinical Trials Register)

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

International audienceThe worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary car-cinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low-and high-grade lung neuroendocrine neoplasms

Protein and amino acid digestibility of 15N Spirulina in rats

International audiencePurpose: Spirulina is often used as dietary supplement for its protein content and quality. However, in vivo data on protein digestibility are lacking. This study aims to determine nitrogen and amino acid digestibility in rats. A secondary objective was to test the effect of sonication prior to ingestion to break cell walls.Methods: Wistar rats were fed a single test meal containing 15N Spirulina that was either sonicated (n = 11) or not (control, n = 13). Rats were euthanized 6 h after the meal ingestion. Spirulina nitrogen digestibility was measured by assessment of 15N recovery in digestive contents. Amino acid digestibility was measured by quantification of the caecal amino acid content and their 15N enrichment.Results: Real fecal nitrogen digestibility was 86.0 ± 0.7%, without any differences between groups. Mean 15N amino acid caecal digestibility was 82.8 ± 1.3%, and values ranged between 77.9 ± 1.9% for serine and 89.4 ± 1.0% for methionine. No effect of sonication was observed. The most limiting AA was histidine, with a chemical score of 0.98 and a PD-CAAS of 0.84. Lysine was also limiting in a lesser extent.Conclusion: The nitrogen and amino acid digestibility of Spirulina is relatively low, and showed no effect of prior sonication. Its amino acid composition is relatively well balanced but not enough to compensate for the poor digestibility

Lipid Phases and Cell Geometry During the Cell Cycle of Streptococcus pneumoniae

International audienceThe coexistence of different lipid phases is well-known , but evidence for their presence and function in cellular membranes remains scarce. Using a combination of fluorescent lipid probes, we observe segregation of domains that suggests the coexistence of liquid and gel phases in the membrane of , where they are localized to minimize bending stress in the ellipsoid geometry defined by the cell wall. Gel phase lipids with high bending rigidity would be spontaneously organized at the equator where curvature is minimal, thus marking the future division site, while liquid phase membrane maps onto the oblong hemispheres. In addition, the membrane-bound cell wall precursor with its particular dynamic acyl chain localizes at the division site where the membrane is highly curved. We propose a complete "chicken-and-egg" model where cell geometry determines the localization of lipid phases that positions the cell division machinery, which in turn alters the localization of lamellar phases by assembling the cell wall with a specific geometry

Biodisponibilité des protéines et des acides aminés de spiruline chez le rat

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Digestive bioavailability of spirulina protein and amino acids in a rat model

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