Abstract
Background
Accumulating evidence links paternal adiposity in the periconceptional period to offspring health outcomes. DNA methylation has been proposed as a mediating mechanism, but very ...few studies have explored this possibility in humans.
Methods
In the Pregnancy And Childhood Epigenetics (PACE) consortium, we conducted a meta-analysis of coordinated epigenome-wide association studies (EWAS) of paternal prenatal body mass index (BMI) (with and without adjustment for maternal BMI) in relation to DNA methylation in offspring blood at birth (13 data sets; total n = 4894) and in childhood (6 data sets; total n = 1982).
Results
We found little evidence of an association at either time point: at all CpGs, the false-discovery-rate-adjusted P-values were >0.05. In secondary sex-stratified analyses, we found just four CpGs for which there was robust evidence of an association in female offspring. To compare our findings to those of other studies, we conducted a systematic review, which identified seven studies, including five candidate gene studies showing associations between paternal BMI/obesity and offspring or sperm DNA methylation at imprinted regions. However, in our own study, we found very little evidence of enrichment for imprinted genes.
Conclusion
Our findings do not support the hypothesis that paternal BMI around the time of pregnancy is associated with offspring-blood DNA methylation, even at imprinted regions.
Recent advances in laboratory sciences hold a promise for a 'leap forward' in understanding the aetiology of complex human diseases, notably cancer, potentially providing an evidence base for ...prevention. For example, remarkable advances in epigenomics have an important impact on our understanding of biological phenomena and importance of environmental stressors in complex diseases. Environmental and lifestyle factors are thought to be implicated in the development of a wide range of human cancers by eliciting changes in the epigenome. These changes, thus, represent attractive targets for biomarker discovery intended for the improvement of exposure and risk assessment, diagnosis and prognosis and provision of short-term outcomes in intervention studies. The epigenome can be viewed as an interface between the genome and the environment; therefore, aberrant epigenetic events associated with environmental exposures are likely to play an important role in the onset and progression of different human diseases. The advent of powerful technologies for analysing epigenetic patterns in both cancer tissues and normal cells holds promise that the next few years will be fundamental for the identification of critical cancer- and exposure-associated epigenetic changes and for their evaluation as new generation of biomarkers. Here, we discuss new opportunities in the current age of 'omics' technologies for studies with prospective design and associated biospecimens that represent exciting potential for characterising the epigenome as a key component of the fetal exposome and for understanding causal pathways and robust predictors of cancer risk and associated environmental determinants during in utero life. Such studies should improve our knowledge concerning the aetiology of childhood cancer and identify both novel biomarkers and clues to causation, thus, providing an evidence base for cancer prevention.
Epigenetic mechanisms are essential for normal development and maintenance of adult life. Disruption of epigenetic processes results in deregulated gene expression and leads to life-threatening ...diseases, in particular, cancer. Global epigenetic alterations are a hallmark of cancer. Cancer epigenetics revealed the deregulation of all components of the epigenetic machinery including DNA methylation, histone modifications, chromatin structure, and non-coding RNAs. Drugs targeting epigenetic processes, or "epi-drugs", are at the forefront of drug discovery, and plant-derived compounds have shown promise. Most of the plant-derived anticancer drugs that work through epigenetic mechanisms are polyphenols; the others are alkaloids, organosulfur compounds, and terpenoids. This review focuses on the epigenetic machinery and its basis for cancer therapy, highlights plant-derived anticancer drugs with epigenetic mechanisms of action, and discusses their potential use in epigenetic therapy.
Maternal exposure to airborne particulate matter (PM) has been associated with restricted fetal growth and reduced birthweight. Here, we performed methylome-wide analyses of cord and children’s blood ...DNA in relation to residential exposure to PM smaller than 10 μm (PM10). This study included participants of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC, cord blood, n = 780; blood at age 7, n = 757 and age 15–17, n = 850) and the EXPOsOMICS birth cohort consortium including cord blood from ENVIRONAGE (n = 197), INMA (n = 84), Piccolipiù (n = 99) and Rhea (n = 75). We could not identify significant CpG sites, by meta-analyzing associations between maternal PM10 exposure during pregnancy and DNA methylation in cord blood, nor by studying DNA methylation and concordant annual exposure at 7 and 15–17 years. The CpG cg21785536 was inversely associated with PM10 exposure using a longitudinal model integrating the three studied age groups (−1.2% per 10 μg/m3; raw p-value = 3.82 × 10–8). Pathway analyses on the corresponding genes of the 100 strongest associated CpG sites of the longitudinal model revealed enriched pathways relating to the GABAergic synapse, p53 signaling and NOTCH1. We provided evidence that residential PM10 exposure in early life affects methylation of the CpG cg21785536 located on the EGF Domain Specific O-Linked N-Acetylglucosamine Transferase gene.
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IJS, KILJ, NUK, PNG, UL, UM
Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 oncoprotein Tax plays an important role in ATL pathogenesis. ATL ...carries a poor prognosis due to chemotherapy resistance, stressing the need for alternative therapies. Here, we investigate the preclinical efficacy of the synthetic retinoid ST1926 in ATL and peripheral T-cell lymphomas. Clinically achievable concentrations of ST1926 induced a dramatic inhibition of cell proliferation in malignant T-cell lines and primary ATL cells with minimal effect on resting or activated normal lymphocytes. ST1926 induced apoptosis, DNA damage, and upregulation of p53 proteins in malignant T cells, whereas it caused an early downregulation of Tax proteins in HTLV-1–positive cells. In murine ATL, oral treatment with ST1926 prolonged survival and reduced leukemia cell infiltration, white blood cell counts, and spleen mass. In spleens of ST1926-treated animals, p53 and p21 proteins were upregulated, poly (ADP-ribose) polymerase was cleaved, and Tax transcripts were reduced. These results highlight the promising use of ST1926 as a targeted therapy for ATL.
•The synthetic retinoid ST1926 induces apoptosis of ATL cells and prolongs survival of ATL mice.•At the molecular level, ST1926 causes early DNA damage, upregulates p53, and downregulates Tax expression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The “delayed infection hypothesis” states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using ...prospectively collected data from six population‐based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 106 person‐years of follow‐up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77–0.99) and 0.85: (0.73–0.99), respectively. Being later‐born was associated with similarly reduced hazards of CL and ALL compared to being first‐born; HRs = 0.78: 95% CI: 0.58–1.05 and 0.73: 0.52–1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later‐born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06–0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures.
What's new?
Can birth order affect childhood leukemia risk? Children with older siblings encounter more infectious pathogens than first‐born children, and fewer childhood infections might contribute to increased risk of childhood leukemia. Here, the authors studied birth order as a proxy for childhood infections. They conducted a prospective study and found that later‐born children had reduced risk of childhood leukemia compared with first‐borns. The effect was strongest in children with fathers age 30 or older, and in children with birth weight less than 3 kg.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Neonatal dried blood spots (DBS) represent an inexpensive method for long-term biobanking worldwide and are considered gold mines for research for several human diseases, including those of ...metabolic, infectious, genetic and epigenetic origin. However, the utility of DBS is restricted by the limited amount and quality of extractable biomolecules (including DNA), especially for genome wide profiling. Degradation of DNA in DBS often occurs during storage and extraction. Moreover, amplifying small quantities of DNA often leads to a bias in subsequent data, particularly in methylome profiles. Thus it is important to develop methodologies that maximize both the yield and quality of DNA from DBS for downstream analyses.
Using combinations of in-house-derived and modified commercial extraction kits, we developed a robust and efficient protocol, compatible with methylome studies, many of which require stringent bisulfite conversion steps. Several parameters were tested in a step-wise manner, including blood extraction, cell lysis, protein digestion, and DNA precipitation, purification and elution. DNA quality was assessed based on spectrophotometric measurements, DNA detectability by PCR, and DNA integrity by gel electrophoresis and bioanalyzer analyses. Genome scale Infinium HumanMethylation450 and locus-specific pyrosequencing data generated using the refined DBS extraction protocol were of high quality, reproducible and consistent.
This study may prove useful to meet the increased demand for research on prenatal, particularly epigenetic, origins of human diseases and for newborn screening programs, all of which are often based on DNA extracted from DBS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The promotion stage in the multistep process of epidermal tumorigenesis is NF-кB-dependent, epigenetically regulated, and reversible, thus, a suitable target for chemoprevention. We investigated ...whether the NF-кB inhibitor, parthenolide, currently in cancer clinical trials, attenuates tumor promotion by modulating the epigenetically regulated NF-кB target genes, p21 and cyclin D1. Parthenolide selectively inhibited the growth of neoplastic keratinocytes while sparing normal ones. Specifically, in JB6P+ cells, a model of tumor promotion, noncytotoxic parthenolide concentrations abrogated tumor promoter-induced cell proliferation and anchorage-independent growth. Furthermore, parthenolide decreased tumor promoter-induced NF-кB activity, increased p21, and decreased cyclin D1 expression. In parthenolide-treated cells, p21 transcription correlated with relaxed chromatin and p65/NF-кB binding at the p21 promoter. However, cyclin D1 transcription correlated more with p65/NF-кB binding than with chromatin structure at the cyclin D1 promoter. Epigenetic regulation by parthenolide seemed specific, as parthenolide did not alter global histone acetylation and methylation and histone deacetylase activity. Because p21 expression by parthenolide was sustained, we used p21-siRNA and p21 -/- cancer cells and showed that the loss of p21 is cytoprotective against parthenolide. Low parthenolide concentrations (0.25 mg/kg) inhibited tumor growth of promoted JB6P+ cells in xenograft immunocompromised mice using two different chemoprevention protocols. Tissue microarray of mouse tumors showed that parthenolide decreased scores of the cell proliferation marker Ki67 and p65/NF-кB, whereas it increased p21 expression. These results show that low doses of parthenolide inhibit tumor promotion and epigenetically modulate p21 expression, highlighting the potential role of this drug as a chemopreventive agent and in epigenetic cancer therapy.
A high body mass (BMI) index has repeatedly been associated with non-atopic asthma, but the biological mechanism linking obesity to asthma is still poorly understood. We aimed to test the hypothesis ...that inflammation and/or innate immunity plays a role in the obesity-asthma link. DNA methylome was measured in blood samples of 61 non-atopic participants with asthma and 146 non-atopic participants without asthma (non-smokers for at least 10 years) taking part in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) study. Modification by DNA methylation of the association of BMI or BMI change over 10 years with adult-onset asthma was examined at each CpG site and differentially methylated region. Pathway enrichment tests were conducted for genes in a priori curated inflammatory pathways and the NLRP3-IL1B-IL17 axis. The latter was chosen on the basis of previous work in mice. Inflammatory pathways including glucocorticoid/PPAR signaling (
= 0.0023), MAPK signaling (
= 0.013), NF-κB signaling (
= 0.031), and PI3K/AKT signaling (
= 0.031) were enriched for the effect modification of BMI, while NLRP3-IL1B-IL17 axis was enriched for the effect modification of BMI change over 10 years (
= 0.046). DNA methylation measured in peripheral blood is consistent with inflammation as a link between BMI and adult-onset asthma and with the NLRP3-IL1B-IL17 axis as a link between BMI change over 10 years and adult-onset asthma in non-atopic participants.
Abstract
Background
Lung neuroendocrine neoplasms (LNENs) are rare solid cancers, with most genomic studies including a limited number of samples. Recently, generating the first multi-omic dataset ...for atypical pulmonary carcinoids and the first methylation dataset for large-cell neuroendocrine carcinomas led us to the discovery of clinically relevant molecular groups, as well as a new entity of pulmonary carcinoids (supra-carcinoids).
Results
To promote the integration of LNENs molecular data, we provide here detailed information on data generation and quality control for whole-genome/exome sequencing, RNA sequencing, and EPIC 850K methylation arrays for a total of 84 patients with LNENs. We integrate the transcriptomic data with other previously published data and generate the first comprehensive molecular map of LNENs using the Uniform Manifold Approximation and Projection (UMAP) dimension reduction technique. We show that this map captures the main biological findings of previous studies and can be used as reference to integrate datasets for which RNA sequencing is available. The generated map can be interactively explored and interrogated on the UCSC TumorMap portal (https://tumormap.ucsc.edu/?p=RCG_lungNENomics/LNEN). The data, source code, and compute environments used to generate and evaluate the map as well as the raw data are available, respectively, in a Nextjournal interactive notebook (https://nextjournal.com/rarecancersgenomics/a-molecular-map-of-lung-neuroendocrine-neoplasms/) and at the EMBL-EBI European Genome-phenome Archive and Gene Expression Omnibus data repositories.
Conclusions
We provide data and all resources needed to integrate them with future LNENs transcriptomic studies, allowing meaningful conclusions to be drawn that will eventually lead to a better understanding of this rare understudied disease.
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