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1. Correlation Patterns Between DNA Methylation and Gene Expression in The Cancer Genome Atlas

   https://doi.org/10.1177/1176935119828776  

   Spainhour, John_CG ; Lim, Hong_Seo ; Yi, Soojin_V ; Qiu, Peng ( February 2019 , Cancer Informatics)

   DNA methylation is a form of epigenetic modification that has been shown to play a significant role in gene regulation. In cancer, DNA methylation plays an important role by regulating the expression of oncogenes. The role of DNA methylation in the onset and progression of various cancer types is now being elucidated as more large-scale data become available. The Cancer Genome Atlas (TCGA) provides a wealth of information for the analysis of various molecular aspects of cancer genetics. Gene expression data and DNA methylation data from TCGA have been used for a variety of studies. A traditional understanding of the effects of DNA methylation on gene expression has linked methylation of CpG sites in the gene promoter region with the decrease in gene expression. Recent studies have begun to expand this traditional role of DNA methylation.

   Here we present a pan-cancer analysis of correlation patterns between CpG methylation and gene expression. Using matching patient data from TCGA, 33 cancer-specific correlations were calculated for each CpG site and the expression level of its corresponding gene. These correlations were used to identify patterns on a per-site basis as well as patterns of methylation across the gene body. Using these identified patterns, we found genes that contain conflicting methylation signals beyond the commonly accepted association between the promoter region methylation and silencing of gene expression. Beyond gene body methylation in whole, we examined individual CpG sites and show that, even in the same gene body, some sites can have a contradictory effect on gene expression in cancers.

   We observed that within promoter regions there was a substantial amount of positive correlation between methylation and gene expression, which contradicts the commonly accepted association. We observed that the correlation between CpG methylation and gene expression does not exhibit in a tissue-specific manner, suggesting that the effects of methylation on gene expression are largely tissue independent. The analysis of correlation associated with the location of the CpG site in the gene body has led to the identification of several different methylation patterns that affect gene expression, and several examples of methylation activating gene expression were observed. Distinctly opposing or conflicting effects were seen in close proximity on the gene body, where negative and positive correlations were seen at the neighboring CpG sites.

    

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2. Human brain region-specific variably methylated regions are enriched for heritability of distinct neuropsychiatric traits

   https://doi.org/10.1186/s13059-021-02335-w  

   Rizzardi, Lindsay F. ; Hickey, Peter F. ; Idrizi, Adrian ; Tryggvadóttir, Rakel ; Callahan, Colin M. ; Stephens, Kimberly E. ; Taverna, Sean D. ; Zhang, Hao ; Ramazanoglu, Sinan ; Hansen, Kasper D. ; et al ( December 2021 , Genome Biology)

   Abstract Background DNA methylation dynamics in the brain are associated with normal development and neuropsychiatric disease and differ across functionally distinct brain regions. Previous studies of genome-wide methylation differences among human brain regions focus on limited numbers of individuals and one to two brain regions. Results Using GTEx samples, we generate a resource of DNA methylation in purified neuronal nuclei from 8 brain regions as well as lung and thyroid tissues from 12 to 23 donors. We identify differentially methylated regions between brain regions among neuronal nuclei in both CpG (181,146) and non-CpG (264,868) contexts, few of which were unique to a single pairwise comparison. This significantly expands the knowledge of differential methylation across the brain by 10-fold. In addition, we present the first differential methylation analysis among neuronal nuclei from basal ganglia tissues and identify unique CpG differentially methylated regions, many associated with ion transport. We also identify 81,130 regions of variably CpG methylated regions, i.e., variable methylation among individuals in the same brain region, which are enriched in regulatory regions and in CpG differentially methylated regions. Many variably methylated regions are unique to a specific brain region, with only 202 common across all brain regions, as well as lung and thyroid. Variably methylated regions identified in the amygdala, anterior cingulate cortex, and hippocampus are enriched for heritability of schizophrenia. Conclusions These data suggest that epigenetic variation in these particular human brain regions could be associated with the risk for this neuropsychiatric disorder. 

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3. The impact of parental and developmental stress on DNA methylation in the avian hypothalamic–pituitary–adrenal axis

   https://doi.org/10.1111/mec.17291  

   Siller Wilks, Stefanie J. ; Heidinger, Britt J. ; Westneat, David F. ; Solomon, Joseph ; Rubenstein, Dustin R. ( February 2024 , Molecular Ecology)

   The hypothalamic–pituitary–adrenal (HPA) axis coordinates an organism's response to environmental stress. The responsiveness and sensitivity of an offspring's stress response may be shaped not only by stressors encountered in their early post‐natal environment but also by stressors in their parent's environment. Yet, few studies have considered how stressors encountered in both of these early life environments may function together to impact the developing HPA axis. Here, we manipulated stressors in the parental and post‐natal environments in a population of house sparrows (Passer domesticus) to assess their impact on changes in DNA methylation (and corresponding gene expression) in a suite of genes within the HPA axis. We found that nestlings that experienced early life stress across both life‐history periods had higher DNA methylation in a critical HPA axis gene, the glucocorticoid receptor (NR3C1). In addition, we found that the life‐history stage when stress was encountered impacted some genes (HSD11B1, NR3C1andNR3C2) differently. We also found evidence for the mitigation of parental stress by post‐natal stress (inHSD11B1andNR3C2). Finally, by assessing DNA methylation in both the brain and blood, we were able to evaluate cross‐tissue patterns. While some differentially methylated regions were tissue‐specific, we found cross‐tissue changes inNR3C2andNR3C1, suggesting that blood is a suitable tissue for assessing DNA methylation as a biomarker of early life stress. Our results provide a crucial first step in understanding the mechanisms by which early life stress in different life‐history periods contributes to changes in the epigenome of the HPA axis.

    

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4. Lifetime stress and war exposure timing may predict methylation changes at NR3C1 based on a pilot study in a warrior cohort in a small‐scale society in Kenya

   https://doi.org/10.1002/ajhb.23515  

   Straight, Bilinda ; Fisher, Georgiana ; Needham, Belinda L. ; Naugle, Amy ; Olungah, Charles ; Wanitjirattikal, Puntipa ; Root, Cecilia ; Farman, Jen ; Barkman, Todd ; Lalancette, Claudia ( October 2020 , American Journal of Human Biology)

   Candidate gene methylation studies of NR3C1 have identified associations with psychosocial adversity, including war trauma. This pilot study (sample sizes from 22 to 45 for primary analyses) examined NR3C1 methylation in a group of Kenyan pastoralist young men in relation to culturally relevant traumatic experiences, including participation in coalitional lethal gun violence.

   Adolescent and young adult Samburu men (“warriors”) were recruited for participation. DNA was obtained from whole saliva and methylation analyses performed using mass spectrometry. We performed a data reduction of variables from a standardized instrument of lifetime stress using a factor analysis and we assessed the association between the extracted factors with culturally relevant and cross‐culturally comparative experiences.

   Cumulative lifetime trauma exposure and forms of violence to which warriors are particularly susceptible were associated with DNA methylation changes in the NR3C1 1_Fpromoter region but not in the NR3C1 1_Dpromoter region. However, sensitivity analyses revealed significant associations between individual CpG sites in both regions and cumulative stress exposures, war exposure timing, and war fatalities.

   This study supports the importance of NR3C1 methylation changes in response to challenging life circumstances, including in a global south cultural context that contrasts in notable ways from global north contexts and from the starkly tragic examples of the Rwandan genocide and war‐associated rape explored in recent studies. Timing of traumatic exposure and culturally salient means to measure enduring symptoms of trauma remain important considerations for DNA methylation studies.

    

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5. Maternal–infant interaction quality is associated with child NR3C1CpG site methylation at 7 years of age

   https://doi.org/10.1002/ajhb.23876  

   Holdsworth, Elizabeth A. ; Schell, Lawrence M. ; Appleton, Allison A. ( February 2023 , American Journal of Human Biology)

   Infancy is both a critical window for hypothalamic–pituitary–adrenal (HPA) axis development, and a sensitive period for social–emotional influences. We hypothesized that the social–emotional quality of maternal–infant interactions are associated with methylation of HPA‐axis geneNR3C1later in childhood.

   Using a subsample of 114 mother‐infant pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC), linear regression models were created to predict variance in methylation of seven selected CpG sites fromNR3C1in whole blood at age 7 years, including the main predictor variable of the first principal component score of observed maternal–infant interaction quality (derived from the Thorpe Interaction Measure at 12 months of age) and covariates of cell‐type proportion, maternal financial difficulties and marital status at 8 months postnatal, child birthweight, and sex.

   CpG site cg27122725 methylation was negatively associated with warmer, more positive maternal interaction with her infant (β = 0.19,p = .02,q = 0.13). In sensitivity analyses, the second highest quartile of maternal behavior (neutral, hesitant behavior) was positively associated with cg12466613 methylation. The other five CpG sites were not significantly associated with maternal–infant interaction quality.

   Narrow individual variation of maternal interaction with her infant is associated with childhood methylation of two CpG sites onNR3C1that may be particularly sensitive to environmental influences. Infancy may be a sensitive period for even small influences from the social–emotional environment on the epigenetic determinants of HPA‐axis function.

    

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