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Background We recently identified ~ 10,000 correlated regions of systemic interindividual epigenetic variation (CoRSIVs) in the human genome. These methylation variants are amenable to population studies, as DNA methylation measurements in blood provide information on epigenetic regulation throughout the body. Moreover, establishment of DNA methylation at human CoRSIVs is labile to periconceptional influences such as nutrition. Here, we analyze publicly available whole-genome bisulfite sequencing data on multiple tissues of each of two Holstein cows to determine whether CoRSIVs exist in cattle. Results Focusing on genomic blocks with ≥ 5 CpGs and a systemic interindividual variation index of at least 20, our approach identifies 217 cattle CoRSIVs, a subset of which we independently validate by bisulfite pyrosequencing. Similar to human CoRSIVs, those in cattle are strongly associated with genetic variation. Also as in humans, we show that establishment of DNA methylation at cattle CoRSIVs is particularly sensitive to early embryonic environment, in the context of embryo culture during assisted reproduction. Conclusions Our data indicate that CoRSIVs exist in cattle, as in humans, suggesting these systemic epigenetic variants may be common to mammals in general. To the extent that individual epigenetic variation at cattle CoRSIVs affects phenotypic outcomes, assessment of CoRSIV methylation at birth may become an important tool for optimizing agriculturally important traits. Moreover, adjusting embryo culture conditions during assisted reproduction may provide opportunities to tailor agricultural outcomes by engineering CoRSIV methylation profiles.

Background Interindividual genetic variability is well characterised, but we still lack a complete catalogue of loci displaying variable and stable epigenetic patterns. Results Here, we report a catalogue of stable and variable interindividual DNA methylation sites in human whole blood by analysing the DNA methylation patterns in 3642 individuals from a representative cohort for the British population using the IlluminaEPIC array. Our results show that 34,972 CpGs display variable methylation levels (VMPs) and 41,216 CpGs display stable methylation. Human whole blood is a widely used tissue in epigenetic research, particularly in Epigenome-Wide Association Studies, due to its accessibility and its ability to provide insights into systemic biological processes and disease mechanisms. This catalogue is a useful resource for interpretation of results when associating epigenetic signals to phenotypes. VMPs are highly enriched in CpG shores, enhancers and intergenic regions and approximately half of the VMPs are under genetic control. Our results also showed that trans mQTL-mCpG pairs (that is a SNP and CpG located > 500bp apart) are often located in the same TAD or connected by chromatin loops. A subset of these VMPs (784) are classified as putative epialleles and there is a link between some of these epialleles located in regulatory regions and gene expression. Conclusions Our study provides of a comprehensive and reliable catalogue of CpG sites displaying variable interindividual DNA methylation across the human epigenome.

Background Epigenetic variations, particularly in response to environmental factors, play a crucial role in shaping immune identity and function in hematopoietic cells. This study investigates interindividual differences in DNA methylation among dairy cows, with the aim of enhancing our understanding of the adaptive capacity essential for sustainable animal production. We conducted whole-genome sequencing and DNA methylation analysis using enzymatic methyl-seq on whole blood from 60 Holstein cows. The study included five phenotype groups: mastitis, lameness, infertility, metabolic disorders and healthy controls. Results Among the 50 million CpG sites, 5.1% were identified as variable methylated cytosines (VMCs) and 94.9% as conserved methylated cytosines (CMCs). VMCs displayed variability in distal promoter regions, suggesting potential plasticity in the associated genes, while CMCs exhibited a bimodal methylation pattern near the transcription start site, indicative of tissue-specific functions. Notably, we identified motif enrichments related to genes potentially expressed in blood. An age-related analysis revealed a 1.4% faster decline in CMCs methylation compared to VMCs. Additionally, disease risk assessment may be achievable using as few as 586 methylation biomarkers, which could be used to select which cows to keep in the herd for additional lactation. Conclusion Our results suggest a dual role for VMCs and CMCs: while the stability of conserved sites is potentially associated with essential functions in cell development and homeostasis, variable sites may be involved in dynamically regulating gene transcription in response to internal or external stimuli. These insights underscore the epigenome’s role in immune regulation and adaptive resilience in cattle.

Background: Occupational exposure to nickel (Ni) is associated with an increased risk for lung and nasal cancers. Ni compounds exhibit weak mutagenic activity, cause gene amplification, and disrupt cellular epigenetic homeostasis. However, the Ni-induced changes in global histone modification levels have only been tested in vitro. Objective: This study was conducted in a Chinese population to determine whether occupational exposure to Ni is associated with alterations of global histone modification levels and to evaluate the inter-and intraindividual variance of global histone modification levels. Method: Forty-five subjects with occupational exposure to Ni and 75 referents were recruited. Urinary Ni and global H3K4 trimethylation, H3K9 acetylation, and H3K9 dimethylation levels were measured in peripheral blood mononuclear cells (PBMCs) of subjects. Results: H3K4me3 was elevated in Ni-exposed subjects (0.25% ± 0.11%) compared with referents (0.15% ± 0.04%; P = 0.0004), and H3K9me2 was decreased (Ni-exposed subjects, 0.11% ± 0.05%; referents, 0.15% ± 0.04%; P= 0.003). H3K4me3 was positively (r = 0.4, p = 0.0008) and H3K9ac was negatively (r = 0.1, P =0.01) associated with urinary Ni. Interindividual variances of H3K4me3, H3K9ac, and H3K9me2 were larger compared with intraindividual variance in both exposure test groups, resulting in reliability coefficients (an estimate of consistency of a set of measurements) of 0.60, 0.67, and 0.79 for H3K4me3, H3K9ac, and H3K9me2, respectively, for Ni-exposed subjects and of 0.75, 0.74, and 0.97, respectively, for referent subjects. Conclusion: The results of this study indicate that occupational exposure to Ni is associated with alterations of global histone modification levels and that measurements of global levels of histone modifications are relatively stable over time in human PBMCs.

Introduction Epigenetic information such as DNA methylation is a useful biomarker that reflects complex gene‐environmental interaction. Peripheral tissues such as blood and saliva are commonly collected as the source of genomic DNA in cohort studies. Epigenetic studies mainly use blood, while a few studies have addressed the epigenetic characteristics of saliva. Methods The effects of methods for DNA extraction and purification from saliva on DNA methylation were surveyed using Illumina Infinium HumanMethylation450 BeadChip. Using 386 661 probes, DNA methylation differences between blood and saliva from 22 healthy volunteers, and their functional and structural characteristics were examined. CpG sites with DNA methylation levels showing large interindividual variations in blood were evaluated using saliva DNA methylation profiles. Results Genomic DNA prepared by simplified protocol from saliva showed a similar quality DNA methylation profile to that derived from the manufacturer provided protocol. Consistent with previous studies, the DNA methylation profiles of blood and saliva showed high correlations. Blood showed 1,514 hypomethylated and 2099 hypermethylated probes, suggesting source‐dependent DNA methylation patterns. CpG sites with large methylation difference between the two sources were underrepresented in the promoter regions and enriched within gene bodies. CpG sites with large interindividual methylation variations in blood also showed considerable variations in saliva. Conclusion In addition to high correlation in DNA methylation profiles, CpG sites showing large interindividual DNA methylation differences were similar between blood and saliva, ensuring saliva could be a suitable alternative source for genomic DNA in cohort studies. Consideration of source‐dependent DNA methylation differences will, however, be necessary. We compared quality of saliva methylome data collected by several DNA purification protocols and examined the characteristics of saliva methylome. Optimized protocol and identified characteristics such as common informative CpG sites to blood and unique epigenetic changes in saliva will contribute to promote the use of saliva for epigenetic studies in clinical settings and epidemiological cohort studies.

Peripheral blood monocytes (PBMs) play multiple and critical roles in the immune response, and abnormalities in PBMs have been linked to a variety of human disorders. However, the DNA methylation landscape in PBMs is largely unknown. In this study, we characterized epigenome-wide DNA methylation profiles in purified PBMs. PBMs were isolated from freshly collected peripheral blood from 18 unrelated healthy postmenopausal Caucasian females. Epigenome-wide DNA methylation profiles (the methylome) were characterized by using methylated DNA immunoprecipitation combined with high-throughput sequencing. Distinct patterns were revealed at different genomic features. For instance, promoters were commonly (∼58%) found to be unmethylated; whereas protein coding regions were largely (∼84%) methylated. Although CpG-rich and -poor promoters showed distinct methylation patterns, interestingly, a negative correlation between promoter methylation levels and gene transcription levels was consistently observed across promoters with high to low CpG densities. Importantly, we observed substantial interindividual variation in DNA methylation across the individual PBM methylomes and the pattern of this interindividual variation varied between different genomic features, with highly variable regions enriched for repetitive DNA elements. Furthermore, we observed a modest but significant excess (p < 2.2 × 10 ) of genes showing a negative correlation between interindividual promoter methylation and transcription levels. These significant genes were enriched in biological processes that are closely related to PBM functions, suggesting that alteration in DNA methylation is likely to be an important mechanism contributing to the interindividual variation in PBM function, and PBM-related phenotypic and disease-susceptibility variation in humans. This study represents a comprehensive analysis of the human PBM methylome and its interindividual variation. Our data provide a valuable resource for future epigenomic and multiomic studies, exploring biological and disease-related regulatory mechanisms in PBMs.