Project description:testes em aulça de metabolomica para fins educativos testes em aulça de metabolomica para fins educativos testes em aulça de metabolomica para fins educativos
Project description:We designed and introduced a new methylation array concentrating on human trait screening and discovery. The new MSA (Methylation Screening Array) leveraged the massive Infinium platform-based data from epigenome-wide association studies, combined with updated knowledge from the latest single cell and cell type-resolution whole genome methylome profiles, to achieve scalable screening of epigenetics-trait association in an ultra-high sample-throughput. Our design encompassed diverse human trait associations, including those with genetic, biological, and demographical variables, environmental exposures, and common human diseases such as neurodegenerative, genetic, cardiovascular, infectious, and immune diseases. We comprehensively evaluated this array's reproducibility, accuracy, and capacity in supporting 5-hydroxymethylation profiling and comprehensive cell-type deconvolution in diverse human tissues. Our first data using this platform uncovered dynamic chromatin and tissue contexts of DNA modification variations and genetic variants with human trait associations.
Project description:Primary objectives: Avaliar a eficácia da abordagem profilática com minociclina no desenvolvimento de toxicidade dermatológica secundária ao cetuximab
Primary endpoints: Percentagem de doentes que desenvolvem rash associado ao tratamento com cetuximab para o cancro colo-rectal, no grupo experimental comparativamente com o grupo controlo
Project description:DNA methylation serves a stable gene regulatory function in mature somatic cells. In the germ line and during early embryogenesis, however, DNA methylation undergoes global erasure and re-establishment to support germ cell and embryonic development. While de novo DNA methylation during male germ cell development is essential for setting genomic imprints, possible other intergenerational roles for paternal DNA methylation following fertilization are unknown. To address this question, we reduced the level of DNA methylation in developing male germ cells through conditional gene deletion of the de novo DNA methyltransferases DNMT3A and DNMT3B in undifferentiated spermatogonia. Mutant male germ cells nevertheless completed their differentiation to sperm. We observed that DNMT3A serves a largely maintenance-like methylation function at many intragenic sites in undifferentiated spermatogonia while DNMT3B catalyzes de novo methylation during spermatogonial differentiation. In spermatogonia, the acquisition of DNA methylation and deposition of H3K4me3 occur mutually exclusive. Failing de novo DNA methylation in spermatogonia leads to increased nucleosome occupancy in mature sperm at sites with high CpG content, reinforcing the model that DNA methylation constrains nucleosome retention in sperm. To assess the impact of altered sperm chromatin in the formation of embryonic chromatin, we measured H3K4me3 occupancy at paternal and maternal alleles in 2-cell embryos using a highly sensitive transposon-based tagging assay for modified chromatin. Our data show that reduced DNA methylation in sperm renders paternal alleles permissive for H3K4me3 establishment in early embryos, independently from paternal inheritance of sperm born H3K4me3. Together, this study provides first evidence that paternally inherited DNA methylation directs chromatin formation during early embryonic development.
Project description:The link between DNA methylation and neurodevelopmental disorders is well established. However, how DNA methylation is fine-tuned – ensuring precise gene expression and developmental fidelity – remains poorly understood. PROSER1, a known TET2 interactor, was recently linked to a severe neurodevelopmental disorder. Here, we demonstrate that PROSER1 interacts with all TET enzymes and stabilizes chromatin-bound TET-OGT-PROSER1-DBHS (TOPD) complexes, which regulate DNA demethylation and developmental gene expression. Surprisingly, we find that PROSER1 also sequesters TET enzymes, preventing widespread demethylation and transposable element de-repression. Our findings identify PROSER1 as a key factor which both positively and negatively regulates DNA demethylation essential for mammalian neurodevelopment.
Project description:Light triggers chloroplast differentiation whereby the etioplast transforms into a photosynthesizing chloroplast and the thylakoid rapidly emerges. However, the sequence of events during chloroplast differentiation remains poorly understood. Here we used whole-seedling proteome data to quantify changes in protein abundances during the course of de-etiolation within the first four days of light exposure. This data complements quantitative lipid and (ultra)structural data described in Pipitone et al. (doi: https://doi.org/10.1101/2020.08.30.274043).
Project description:Long known as the site of ribosome biogenesis, the nucleolus is increasingly recognized for its role in shaping 3D genome organization. Still, the mechanisms governing the targeting of selected regions of the genome to nucleolus-associated domains (NADs) remain enigmatic. Here we reveal the essential role of ZNF274, a SCAN-bearing member of the Krüppel-associated box (KRAB)-containing zinc finger proteins (KZFP) family, in sequestering lineage-specific gene clusters within NADs. Ablation of ZNF274 triggers transcriptional activation across entire genomic neighborhoods – encompassing, among others, protocadherin and KZFP-encoding genes – with loss of repressive chromatin marks, altered 3D genome architecture and de novo CTCF binding. Mechanistically, ZNF274 anchors target DNA sequences at the nucleolus and facilitates their compartmentalization via a previously uncharted function of the SCAN domain. Our findings illuminate the mechanisms underlying NADs organization and suggest that perinucleolar entrapment into repressive hubs constrains the activation of tandemly arrayed genes to enable selective expression and modulate cell differentiation programs during development.
Project description:Interventions: ultra low dose CT colonography
Primary outcome(s): Per-patient performance of CT ultra low dose colonography in the detection of neoplasms, with colonoscopy results as the reference standard.
Study Design: Single arm Non-randomized