Maternal caffeine consumption during pregnancy and offspring cord blood DNA methylation:an epigenome-wide association study meta-analysis

Background: Prenatal caffeine exposure may influence offspring health via DNA methylation, but no large studies have tested this. Materials &amp; methods: Epigenome-wide association studies and differentially methylated regions in cord blood (450k or EPIC Illumina arrays) were meta-analyzed across six European cohorts (n = 3725). Differential methylation related to self-reported caffeine intake (mg/day) from coffee, tea and cola was compared with assess whether caffeine is driving effects. Results: One CpG site (cg19370043, PRRX1) was associated with caffeine and another (cg14591243, STAG1) with cola intake. A total of 12-22 differentially methylated regions were detected with limited overlap across caffeinated beverages. Conclusion: We found little evidence to support an intrauterine effect of caffeine on offspring DNA methylation. Statistical power limitations may have impacted our findings. </p

Multi-Omics Analysis Reveals MicroRNAs Associated With Cardiometabolic Traits

MicroRNAs (miRNAs) are non-coding RNA molecules that regulate gene expression. Extensive research has explored the role of miRNAs in the risk for type 2 diabetes (T2D) and

Strategies for validation and testing of DNA methylation biomarkers

DNA methylation is a stable covalent epigenetic modification of primarily CpG dinucleotides that has recently gained considerable attention for its use as a biomarker in different clinical settings, including disease diagnosis, prognosis and therapeutic response prediction. Although the advent of genome-wide DNA methylation profiling in primary disease tissue has provided a manifold resource for biomarker development, only a tiny fraction of DNA methylation-based assays have reached clinical testing. Here, we provide a critical overview of different analytical methods that are suitable for biomarker validation, including general study design considerations, which might help to streamline epigenetic marker development. Furthermore, we highlight some of the recent marker validation studies and established markers that are currently commercially available for assisting in clinical management of different cancers

Novel Molecular Characteristics of Ulcerative Colitis

Ulcerative Colitis (UC) is a chronic autoimmune inflammatory disease and one type of inflammatory bowel disease (IBD). UC is characterized by a temporal course of remission and relapse. Environmental factors, immune system dysregulation, and genetic susceptibility interact intricately in the aetiology of UC. It is unclear how interactions involving non-coding RNAs (ncRNAs), epigenetic modifications, and genetic changes relate to active UC, remission, and relapse. The inability to predict relapse in patients with UC poses a challenge to current treatment options. Visible disease manifestations, which are usually absent in patients in remission, frequently place limitations on the use of clinical diagnostic methods. Thus, it is necessary to characterize remission at the molecular level. To investigate the molecular mechanisms in remission and active UC, data from whole transcriptome sequencing (RNA-seq) and whole genome bisulfite sequencing (WGBS) of mucosal biopsies have been analysed with a variety of bioinformatic methods The analyses resulted in the identification of a set of mitochondrial RNAs and small nuclear RNAs (snoRNAs) which may influence the duration of remission. Several identified remission-specific genes are involved in pro- and anti-inflammatory pathways and some of the identified genes may be regulated by DNA methylation. In addition, several DNA-methylated long non-coding RNAs (lncRNAs) have been found to be involved in UC inflammatory immune responses. These findings might shed light on the pathophysiology of UC and suggest new diagnostic markers

Epigenomics of Sarcomas

Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukemia (AML), lower-grade glioma (LGG), and cholangiocarcinoma (CC). In these three malignancies, mutant IDH status is associated with increased 2-hydroxyglutarate (2-HG) production and a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here I show that the IDH variants in chondrosarcoma (CS) are also associated with a hypermethylation phenotype, supporting the role of mutant IDH-produced 2-HG as an inhibitor of TET-mediated DNA demethylation. The associated gene expression profile is also investigated, highlighting the need for a better understanding of DNA methylation-mediated transcriptional regulation. The generated methylation data is additionally harnessed to reveal novel copy number variants in CS. Meta-analysis of the AML, LGG, CC and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, I identify the transcription factor EBF1 as an interaction partner for TET2, in the first description of a targeted demethylation pathway. In an effort to assess whether patient-derived tumour xenografts (PDXs) are suitable models for epigenetic research in rare and common cancers, such as osteosarcoma (OS) and colon cancer, respectively, I compare PDXs to their matched patient tumour and reveal that an average of only 2.7% of the assayed methylome undergoes major methylation changes with xenografting. In addition, no further changes are identified in subsequent PDX generations, making these models highly suitable for expansion of rare tumours and preclinical drug screening. Finally I propose a model to inform future study design and statistically dilute those methylation shifts identified in PDXs

The emerging landscape of dynamic DNA methylation in early childhood

Background: DNA methylation has been found to associate with disease, aging and environmental exposure, but it is unknown how genome, environment and disease influence DNA methylation dynamics in childhood. Results: By analysing 538 paired DNA blood samples from children at birth and at 4-5 years old and 726 paired samples from children at 4 and 8 years old from four European birth cohorts using the Illumina Infinium Human Methylation 450 k chip, we have identified 14,150 consistent age-differential methylation sites (a-DMSs) at epigenome-wide significance of rho <1.14x10(-7). Genes with an increase in age-differential methylation were enriched in pathways related to 'development', and were more often located in bivalent transcription start site (TSS) regions, which can silence or activate expression of developmental genes. Genes with a decrease in age-differential methylation were involved in cell signalling, and enriched on H3K27ac, which can predict developmental state. Maternal smoking tended to decrease methylation levels at the identified da-DMSs. We also found 101 a-DMSs (0.71%) that were regulated by genetic variants using cis-differential Methylation Quantitative Trait Locus (cis-dMeQTL) mapping. Moreover, a-DMS-associated genes during early development were significantly more likely to be linked with disease. Conclusion: Our study provides new insights into the dynamic epigenetic landscape of the first 8 years of life.Peer reviewe

Longitudinal assessment of neuronal 3D genomes in mouse prefrontal cortex

Neuronal epigenomes, including chromosomal loopings moving distal cis-regulatory elements into proximity of target genes, could serve as molecular proxy linking present-day-behaviour to past exposures. However, longitudinal assessment of chromatin state is challenging, because conventional chromosome conformation capture assays essentially provide single snapshots at a given time point, thus reflecting genome organization at the time of brain harvest and therefore are non-informative about the past. Here we introduce ‘NeuroDam’ to assess epigenome status retrospectively. Short-term expression of the bacterial DNA adenine methyltransferase Dam, tethered to the Gad1 gene promoter in mouse prefrontal cortex neurons, results in stable G[superscriptmethyl]ATC tags at Gad1-bound chromosomal contacts. We show by NeuroDam that mice with defective cognition 4 months after pharmacological NMDA receptor blockade already were affected by disrupted chromosomal conformations shortly after drug exposure. Retrospective profiling of neuronal epigenomes is likely to illuminate epigenetic determinants of normal and diseased brain development in longitudinal context.United States. National Institutes of Healt

Epigenetic control of microglial immune responses

Microglia, the major population of brain-resident macrophages, are now recognized as a heterogeneous population comprising several cell subtypes with different (so far mostly supposed) functions in health and disease. A number of studies have performed molecular characterization of these different microglial activation states over the last years making use of omics technologies, that is transcriptomics, proteomics and, less frequently, epigenomics profiling. These approaches offer the possibility to identify disease mechanisms, discover novel diagnostic biomarkers, and develop new therapeutic strategies. Here, we focus on epigenetic profiling as a means to understand microglial immune responses beyond what other omics methods can offer, that is, revealing past and present molecular responses, gene regulatory networks and potential future response trajectories, and defining cell subtype-specific disease relevance through mapping non-coding genetic variants. We review the current knowledge in the field regarding epigenetic regulation of microglial identity and function, provide an exemplary analysis that demonstrates the advantages of performing joint transcriptomic and epigenomic profiling of single microglial cells and discuss how comprehensive epigenetic analyses may enhance our understanding of microglial pathophysiology