Development of a Novel NGS Methodology for Ultrasensitive Circulating Tumor DNA Detection as a Tool for Early-Stage Breast Cancer Diagnosis.

Breast cancer (BC) is the most prevalent cancer in women. While usually detected when localized, invasive procedures are still required for diagnosis. Herein, we developed a novel ultrasensitive pipeline to detect circulating tumor DNA (ctDNA) in a series of 75 plasma samples from localized BC patients prior to any medical intervention.

Identification of human mitochondrial RNA cleavage sites and candidate RNA processing factors.

Background: The human mitochondrial genome is transcribed as long strands of RNA containing multiple genes, which require post-transcriptional cleavage and processing to release functional gene products that play vital roles in cellular energy production. Despite knowledge implicating mitochondrial post-transcriptional processes in pathologies such as cancer, cardiovascular disease and diabetes, very little is known about the way their function varies on a human population level and what drives changes in these processes to ultimately influence disease risk. Here, we develop a method to detect and quantify mitochondrial RNA cleavage events from standard RNA sequencing data and apply this approach to human whole blood data from > 1000 samples across independent cohorts.

Nuclear genetic regulation of the human mitochondrial transcriptome.

Mitochondria play important roles in cellular processes and disease, yet little is known about how the transcriptional regime of the mitochondrial genome varies across individuals and tissues. By analyzing >11,000 RNA-sequencing libraries across 36 tissue/cell types, we find considerable variation in mitochondrial-encoded gene expression along the mitochondrial transcriptome, across tissues and between individuals, highlighting the importance of cell-type specific and post-transcriptional processes in shaping mitochondrial-encoded RNA levels. Using whole-genome genetic data we identify 64 nuclear loci associated with expression levels of 14 genes encoded in the mitochondrial genome, including missense variants within genes involved in mitochondrial function (, and ), implicating genetic mechanisms that act in across the two genomes.

Loss of Trem2 in microglia leads to widespread disruption of cell coexpression networks in mouse brain.

Rare heterozygous coding variants in the triggering receptor expressed in myeloid cells 2 (TREM2) gene, conferring increased risk of developing late-onset Alzheimer's disease, have been identified. We examined the transcriptional consequences of the loss of Trem2 in mouse brain to better understand its role in disease using differential expression and coexpression network analysis of Trem2 knockout and wild-type mice. We generated RNA-Seq data from cortex and hippocampus sampled at 4 and 8 months.

Early-life nutrition modulates the epigenetic state of specific rDNA genetic variants in mice.

A suboptimal early-life environment, due to poor nutrition or stress during pregnancy, can influence lifelong phenotypes in the progeny. Epigenetic factors are thought to be key mediators of these effects. We show that protein restriction in mice from conception until weaning induces a linear correlation between growth restriction and DNA methylation at ribosomal DNA (rDNA).

Protection against de novo methylation is instrumental in maintaining parent-of-origin methylation inherited from the gametes.

Identifying loci with parental differences in DNA methylation is key to unraveling parent-of-origin phenotypes. By conducting a MeDIP-Seq screen in maternal-methylation free postimplantation mouse embryos (Dnmt3L-/+), we demonstrate that maternal-specific methylation exists very scarcely at midgestation. We reveal two forms of oocyte-specific methylation inheritance: limited to preimplantation, or with longer duration, i.

Comparative methylomics reveals gene-body H3K36me3 in Drosophila predicts DNA methylation and CpG landscapes in other invertebrates.

In invertebrates that harbor functional DNA methylation enzymatic machinery, gene-bodies are the primary targets for CpG methylation. However, virtually all other aspects of invertebrate DNA methylation have remained a mystery until now. Here, using a comparative methylomics approach, we demonstrate that Nematostella vectensis, Ciona intestinalis, Apis mellifera, and Bombyx mori show two distinct populations of genes differentiated by gene-body CpG density.

Bionemo: molecular information on biodegradation metabolism.

Bionemo (http://bionemo.bioinfo.cnio.