Publications by authors named "Michael S Kobor"

174 Publications

Maternal psychosocial risk factors and child gestational epigenetic age in a South African birth cohort study.

Transl Psychiatry 2021 07 2;11(1):358. Epub 2021 Jul 2.

Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.

Accelerated epigenetic aging relative to chronological age has been found to be associated with higher risk of mortality in adults. However, little is known about whether and how in utero exposures might shape child gestational epigenetic age (EA) at birth. We aimed to explore associations between maternal psychosocial risk factors and deviation in child gestational EA at birth (i.e., greater or lower EA relative to chronological age) in a South African birth cohort study-the Drakenstein Child Health Study. Maternal psychosocial risk factors included trauma/stressor exposure; posttraumatic stress disorder (PTSD); depression; psychological distress; and alcohol/tobacco use. Child gestational EA at birth was calculated using an epigenetic clock previously devised for neonates; and gestational EA deviation was calculated as the residuals of the linear model between EA and chronological gestational age. Bivariate linear regression was then used to explore unadjusted associations between maternal/child risk factors and child gestational EA residuals at birth. Thereafter, a multivariable regression method was used to determine adjusted associations. Data from 271 maternal-child dyads were included in the current analysis. In the multivariable regression model, maternal PTSD was significantly and negatively associated with child gestational EA residuals at birth (β = -1.95; p = 0.018), controlling for study site, sex of the child, head circumference at birth, birthweight, mode of delivery, maternal estimated household income, body mass index (BMI) at enrolment, HIV status, anaemia, psychological distress, and prenatal tobacco or alcohol use. Given the novelty of this preliminary finding, and its potential translational relevance, further studies to delineate underlying biological pathways and to explore clinical implications of EA deviation are warranted.
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http://dx.doi.org/10.1038/s41398-021-01434-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253754PMC
July 2021

Associations of peripheral blood DNA methylation and estimated monocyte proportion differences during infancy with toddler attachment style.

Attach Hum Dev 2021 Jul 1:1-30. Epub 2021 Jul 1.

Department of Pediatrics, University of Calgary, Calgary, Canada.

Attachment is a motivational system promoting felt security to a caregiver resulting in a persistent internal working model of interpersonal behavior. Attachment styles are developed in early social environments and predict future health and development outcomes with potential biological signatures, such as epigenetic modifications like DNA methylation (DNAm). Thus, we hypothesized infant DNAm would associate with toddler attachment styles. An epigenome-wide association study (EWAS) of blood DNAm from 3-month-old infants was regressed onto children's attachment style from the Strange Situation Procedure at 22-months at multiple DNAm Cytosine-phosphate-Guanine (CpG) sites. The 26 identified CpGs associated with proinflammatory immune phenotypes and cognitive development. In post-hoc analyses, only maternal cognitive-growth fostering, encouraging intellectual exploration, contributed. For disorganized children, DNAm-derived cell-type proportions estimated higher monocytes -cells in immune responses hypothesized to increase with early adversity. Collectively, these findings suggested the potential biological embedding of both adverse and advantageous social environments as early as 3-months-old.
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http://dx.doi.org/10.1080/14616734.2021.1938872DOI Listing
July 2021

DNA methylation differences associated with social anxiety disorder and early life adversity.

Transl Psychiatry 2021 02 4;11(1):104. Epub 2021 Feb 4.

Department of Psychiatry and Psychotherapy, Eberhard Karls University of Tübingen, Tübingen, Germany.

Social anxiety disorder (SAD) is a psychiatric disorder characterized by extensive fear in social situations. Multiple genetic and environmental factors are known to contribute to its pathogenesis. One of the main environmental risk factors is early life adversity (ELA). Evidence is emerging that epigenetic mechanisms such as DNA methylation might play an important role in the biological mechanisms underlying SAD and ELA. To investigate the relationship between ELA, DNA methylation, and SAD, we performed an epigenome-wide association study for SAD and ELA examining DNA from whole blood of a cohort of 143 individuals using DNA methylation arrays. We identified two differentially methylated regions (DMRs) associated with SAD located within the genes SLC43A2 and TNXB. As this was the first epigenome-wide association study for SAD, it is worth noting that both genes have previously been associated with panic disorder. Further, we identified two DMRs associated with ELA within the SLC17A3 promoter region and the SIAH3 gene and several DMRs that were associated with the interaction of SAD and ELA. Of these, the regions within C2CD2L and MRPL28 showed the largest difference in DNA methylation. Lastly, we found that two DMRs were associated with both the severity of social anxiety and ELA, however, neither of them was found to mediate the contribution of ELA to SAD later in life. Future studies are needed to replicate our findings in independent cohorts and to investigate the biological pathways underlying these effects.
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http://dx.doi.org/10.1038/s41398-021-01225-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862482PMC
February 2021

Epigenetic Age Acceleration and Risk for Posttraumatic Stress Disorder following Exposure to Substantiated Child Maltreatment.

J Clin Child Adolesc Psychol 2021 Jan 20:1-11. Epub 2021 Jan 20.

Department of Human Development and Family Studies, The Pennsylvania State University.

: Child maltreatment is among the strongest predictors of posttraumatic stress disorder (PTSD). However, less than 40% of children who have been maltreated are ever diagnosed with PTSD, suggesting that exposure to child maltreatment alone is insufficient to explain this risk. This study examined whether epigenetic age acceleration, a stress-sensitive biomarker derived from DNA methylation, explains variation in PTSD diagnostic status subsequent to child maltreatment.: Children and adolescents ( = 70; 65.7% female), 8-15 years of age ( = 12.00,  = 2.37) and exposed to substantiated child maltreatment within the 12 months prior to study entry, were enrolled. Participants provided epithelial cheek cells via buccal swab for genotyping and quantification of epigenetic age acceleration within a case-control design. PTSD diagnostic status was determined using the Child PTSD Symptoms Scale according to the DSM-IV-TR algorithm.: Epigenetic age acceleration predicted current PTSD status, revealing an effect size magnitude in the moderate range,  = 2.35, : 1.22- 4.51, after adjusting for sample demographics, polygenic risk for PTSD, and lifetime exposure to other childhood adversities. Supplemental analyses demonstrated that epigenetic age acceleration was related to a greater severity of PTSD arousal symptoms ( =.29, =.015). There were no differential effects for child maltreatment subtype on epigenetic age acceleration or PTSD status.: The biological embedding of child maltreatment may explain variation in PTSD diagnostic status and serve as a novel approach for informing selective prevention or precision-based therapeutics for those at risk for PTSD.
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http://dx.doi.org/10.1080/15374416.2020.1864738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289945PMC
January 2021

Internalizing symptoms associate with the pace of epigenetic aging in childhood.

Biol Psychol 2021 02 15;159:108021. Epub 2021 Jan 15.

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, the Netherlands.

Childhood psychiatric symptoms may be associated with advanced biological aging. This study examined whether epigenetic age acceleration (EAA) associates with internalizing and externalizing symptoms that were prospectively collected across childhood in a longitudinal cohort study. At age 6 buccal epithelial cells from 148 children (69 girls) were collected to survey genome-wide DNA methylation. EAA was estimated using the Horvath clock. Internalizing symptoms at ages 2.5 and 4 years significantly predicted higher EAA at age 6, which in turn was significantly associated with internalizing symptoms at ages 6-10 years. Similar trends for externalizing symptoms did not reach statistical significance. These findings indicate advanced biological aging in relation to child mental health and may help better identify those at risk for lasting impairments associated with internalizing disorders.
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http://dx.doi.org/10.1016/j.biopsycho.2021.108021DOI Listing
February 2021

Maternal antenatal depression and child mental health: Moderation by genomic risk for attention-deficit/hyperactivity disorder.

Dev Psychopathol 2020 12;32(5):1810-1821

Douglas Research Centre, Department of Psychiatry, McGill University, Montreal, QC, Canada.

Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture the genotypic influence. We outline a novel approach to describe genomic susceptibility to maternal antenatal depression focusing on child emotional/behavioral difficulties. Two cohorts provided measures of maternal depression, child genetic variation, and child mental health symptoms. We constructed a conventional polygenic risk score (PRS) for attention-deficit/hyperactivity disorder (ADHD) (PRSADHD) that significantly moderated the association between maternal antenatal depression and internalizing problems at 60 months (p = 2.94 × 10-4, R2 = .18). We then constructed an interaction PRS (xPRS) based on a subset of those single nucleotide polymorphisms from the PRSADHD that most accounted for the moderation of the association between maternal antenatal depression and child outcome. The interaction between maternal antenatal depression and this xPRS accounted for a larger proportion of the variance in child emotional/behavioral problems than models based on any PRSADHD (p = 5.50 × 10-9, R2 = .27), with similar findings in the replication cohort. The xPRS was significantly enriched for genes involved in neuronal development and synaptic function. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health.
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http://dx.doi.org/10.1017/S0954579420001418DOI Listing
December 2020

Multi-Omic Data Integration Allows Baseline Immune Signatures to Predict Hepatitis B Vaccine Response in a Small Cohort.

Front Immunol 2020 30;11:578801. Epub 2020 Nov 30.

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.

Background: Vaccination remains one of the most effective means of reducing the burden of infectious diseases globally. Improving our understanding of the molecular basis for effective vaccine response is of paramount importance if we are to ensure the success of future vaccine development efforts.

Methods: We applied cutting edge multi-omics approaches to extensively characterize temporal molecular responses following vaccination with hepatitis B virus (HBV) vaccine. Data were integrated across cellular, epigenomic, transcriptomic, proteomic, and fecal microbiome profiles, and correlated to final HBV antibody titres.

Results: Using both an unsupervised molecular-interaction network integration method (NetworkAnalyst) and a data-driven integration approach (DIABLO), we uncovered baseline molecular patterns and pathways associated with more effective vaccine responses to HBV. Biological associations were unravelled, with signalling pathways such as JAK-STAT and interleukin signalling, Toll-like receptor cascades, interferon signalling, and Th17 cell differentiation emerging as important pre-vaccination modulators of response.

Conclusion: This study provides further evidence that baseline cellular and molecular characteristics of an individual's immune system influence vaccine responses, and highlights the utility of integrating information across many parallel molecular datasets.
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http://dx.doi.org/10.3389/fimmu.2020.578801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734088PMC
June 2021

Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria.

Cell 2020 12 8;183(7):1826-1847.e31. Epub 2020 Dec 8.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Necker Hospital for Sick Children, 75015 Paris, France; University of Paris, Imagine Institute, 75015 Paris, France.

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2 γδ T lymphocytes, and of Mycobacterium-non reactive classic T1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8 αβ T and non-classic CD4 αβ T1 lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2 γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8 αβ T, and CD4 αβ T1 cells unable to compensate for this deficit.
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http://dx.doi.org/10.1016/j.cell.2020.10.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770098PMC
December 2020

Systems Biology Methods Applied to Blood and Tissue for a Comprehensive Analysis of Immune Response to Hepatitis B Vaccine in Adults.

Front Immunol 2020 4;11:580373. Epub 2020 Nov 4.

Department of Radiology, BC Children's Hospital, Vancouver, BC, Canada.

Conventional vaccine design has been based on trial-and-error approaches, which have been generally successful. However, there have been some major failures in vaccine development and we still do not have highly effective licensed vaccines for tuberculosis, HIV, respiratory syncytial virus, and other major infections of global significance. Approaches at rational vaccine design have been limited by our understanding of the immune response to vaccination at the molecular level. Tools now exist to undertake in-depth analysis using systems biology approaches, but to be fully realized, studies are required in humans with intensive blood and tissue sampling. Methods that support this intensive sampling need to be developed and validated as feasible. To this end, we describe here a detailed approach that was applied in a study of 15 healthy adults, who were immunized with hepatitis B vaccine. Sampling included ~350 mL of blood, 12 microbiome samples, and lymph node fine needle aspirates obtained over a ~7-month period, enabling comprehensive analysis of the immune response at the molecular level, including single cell and tissue sample analysis. Samples were collected for analysis of immune phenotyping, whole blood and single cell gene expression, proteomics, lipidomics, epigenetics, whole blood response to key immune stimuli, cytokine responses, T cell responses, antibody repertoire analysis and the microbiome. Data integration was undertaken using different approaches-NetworkAnalyst and DIABLO. Our results demonstrate that such intensive sampling studies are feasible in healthy adults, and data integration tools exist to analyze the vast amount of data generated from a multi-omics systems biology approach. This will provide the basis for a better understanding of vaccine-induced immunity and accelerate future rational vaccine design.
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http://dx.doi.org/10.3389/fimmu.2020.580373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672042PMC
June 2021

Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial.

PLoS Med 2020 11 5;17(11):e1003229. Epub 2020 Nov 5.

Biological Sciences, Institute of Developmental Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom.

Background: Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia.

Methods And Findings: We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders.

Conclusions: Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings.

Trial Registration: ISRCTN89971375.
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http://dx.doi.org/10.1371/journal.pmed.1003229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643947PMC
November 2020

TWIST1 DNA methylation is a cell marker of airway and parenchymal lung fibroblasts that are differentially methylated in asthma.

Clin Epigenetics 2020 10 2;12(1):145. Epub 2020 Oct 2.

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.

Background: Mesenchymal fibroblasts are ubiquitous cells that maintain the extracellular matrix of organs. Within the lung, airway and parenchymal fibroblasts are crucial for lung development and are altered with disease, but it has been difficult to understand their roles due to the lack of distinct molecular markers. We studied genome-wide DNA methylation and gene expression in airway and parenchymal lung fibroblasts from healthy and asthmatic donors, to identify a robust cell marker and to determine if these cells are molecularly distinct in asthma.

Results: Airway (N = 8) and parenchymal (N = 15) lung fibroblasts from healthy individuals differed in the expression of 158 genes, and DNA methylation of 3936 CpGs (Bonferroni adjusted p value < 0.05). Differential DNA methylation between cell types was associated with differential expression of 42 genes, but no single DNA methylation CpG feature (location, effect size, number) defined the interaction. Replication of gene expression and DNA methylation in a second cohort identified TWIST1 gene expression, DNA methylation and protein expression as a cell marker of airway and parenchymal lung fibroblasts, with DNA methylation having 100% predictive discriminatory power. DNA methylation was differentially altered in parenchymal (112 regions) and airway fibroblasts (17 regions) with asthmatic status, with no overlap between regions.

Conclusions: Differential methylation of TWIST1 is a robust cell marker of airway and parenchymal lung fibroblasts. Airway and parenchymal fibroblast DNA methylation are differentially altered in individuals with asthma, and the role of both cell types should be considered in the pathogenesis of asthma.
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http://dx.doi.org/10.1186/s13148-020-00931-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531162PMC
October 2020

Occurrence of Accelerated Epigenetic Aging and Methylation Disruptions in Human Immunodeficiency Virus Infection Before Antiretroviral Therapy.

J Infect Dis 2021 May;223(10):1681-1689

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Whether accelerated aging develops over the course of chronic human immunodeficiency virus (HIV) infection or can be observed before significant immunosuppression on is unknown. We studied DNA methylation in blood to estimate cellular aging in persons living with HIV (PLWH) before the initiation of antiretroviral therapy (ART).

Methods: A total of 378 ART-naive PLWH who had CD4 T-cell counts >500/µL and were enrolled in the Strategic Timing of Antiretroviral Therapy trial (Pulmonary Substudy) were compared with 34 HIV-negative controls. DNA methylation was performed using the Illumina MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and differentially methylated regions (DMRs) in PLWH compared with controls were identified using a robust linear model. Methylation age was calculated using a previously described epigenetic clock.

Results: There were a total of 56 639 DMPs and 6103 DMRs at a false discovery rate of <0.1. The top 5 DMPs corresponded to genes NLRC5, VRK2, B2M, and GPR6 and were highly enriched for cancer-related pathways. PLWH had significantly higher methylation age than HIV-negative controls (P = .001), with black race, low CD4 and high CD8 T-cell counts, and duration of HIV being risk factors for age acceleration.

Conclusions: PLWH before the initiation of ART and with preserved immune status show evidence of advanced methylation aging.
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http://dx.doi.org/10.1093/infdis/jiaa599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161637PMC
May 2021

Methylation of cysteinyl leukotriene receptor 1 genes associates with lung function in asthmatics exposed to traffic-related air pollution.

Epigenetics 2021 Jan-Feb;16(2):177-185. Epub 2020 Jul 12.

Department of Medicine, P: 604-875-4729, University of British Columbia , Vancouver, BC, Canada.

Air pollution is associated with early declines in lung function and increased levels of asthma-related cysteinyl leukotrienes (CysLT) but a biological pathway linking this rapid response has not been delineated. In this randomized controlled diesel exhaust (DE) challenge study of 16 adult asthmatics, increased exposure-attributable urinary leukotriene E4 (uLTE4, a biomarker of cysteinyl leukotriene production) was correlated (p = 0.04) with declines in forced expiratory volume in 1-second (FEV) within 6 hours of exposure. Exposure-attributable uLTE4 increases were correlated (p = 0.02) with increased CysLT receptor 1 (CysLTR1) methylation in peripheral blood mononuclear cells which, in turn, was marginally correlated (p = 0.06) with decreased CysLTR1 expression. Decreased CysLTR1 expression was, in turn, correlated (p = 0.0007) with FEV declines. During the same time period, increased methylation of GPR17 (a negative regulator of CysLTR1) was observed after DE exposure (p = 0.02); this methylation increase was correlated (p = 0.001) with decreased CysLTR1 methylation which, in turn, was marginally correlated (p = 0.06) with increased CysLTR1 expression; increased CysLTR1 expression was correlated (p = 0.0007) with FEV increases. Collectively, these data delineate a potential mechanistic pathway linking increased DE exposure-attributable CysLT levels to lung function declines through changes in CysLTR1-related methylation and gene expression.
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http://dx.doi.org/10.1080/15592294.2020.1790802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889228PMC
July 2020

Amygdala 5-HTT Gene Network Moderates the Effects of Postnatal Adversity on Attention Problems: Anatomo-Functional Correlation and Epigenetic Changes.

Front Neurosci 2020 17;14:198. Epub 2020 Mar 17.

Integrated Program in Neuroscience (IPN), McGill University, Montreal, QC, Canada.

Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children.
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http://dx.doi.org/10.3389/fnins.2020.00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093057PMC
March 2020

Neonatal Alcohol Exposure in Mice Induces Select Differentiation- and Apoptosis-Related Chromatin Changes Both Independent of and Dependent on Sex.

Front Genet 2020 11;11:35. Epub 2020 Feb 11.

Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital Research Institute - Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.

Prenatal alcohol exposure (PAE) affects many aspects of physiology and behavior, including brain development. Specifically, ethanol can influence expression of genes important for brain growth, including chromatin modifiers. Ethanol can also increase apoptotic cell death in the brain and alter epigenetic profiles such as modifications to histones and DNA methylation. Although differential sex outcomes and disruptions to the function of multiple brain regions have been reported in fetal alcohol spectrum disorder (FASD), the majority of our knowledge on molecular epigenetic and apoptotic dysregulation in PAE is based on data from males and is sometimes limited to assessments of the whole brain or one brain region. Here, we examined histone modifications, DNA methylation, and expression of genes involved in differentiation and proliferation related-chromatin modifications and apoptosis in the cerebral cortex and cerebellum of C57BL/6J mice exposed to an acute alcohol challenge on postnatal day 7, with a focus on differential outcomes between sexes and brain regions. We found that neonatal alcohol exposure altered histone modifications, and impacted expression of a select few chromatin modifier and apoptotic genes in both the cortex and cerebellum. The results were observed primarily in a sex-independent manner, although some additional trends toward sexual dimorphisms were observed. Alcohol exposure induced trends toward increased bulk H3K4me3 levels, increased expression, and elevated levels of mRNA and bulk γH2A.X. Additional trends indicated that ethanol may impact promoter DNA methylation levels and bulk levels of the histone variant H2A.Z, although further studies are needed. We comprehensively examined effects of ethanol exposure across different sexes and brain regions, and our results suggest that major impacts of ethanol on bulk chromatin modifications underlying differentiation and apoptosis may be broadly applicable across the rodent cortex and cerebellum in both sexes.
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http://dx.doi.org/10.3389/fgene.2020.00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026456PMC
February 2020

CoMeBack: DNA methylation array data analysis for co-methylated regions.

Bioinformatics 2020 05;36(9):2675-2683

BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.

Motivation: High-dimensional DNA methylation (DNAm) array coverage, while sparse in the context of the entire DNA methylome, still constitutes a very large number of CpG probes. The ensuing multiple-test corrections affect the statistical power to detect associations, likely contributing to prevalent limited reproducibility. Array probes measuring proximal CpG sites often have correlated levels of DNAm that may not only be biologically meaningful but also imply statistical dependence and redundancy. New methods that account for such correlations between adjacent probes may enable improved specificity, discovery and interpretation of statistical associations in DNAm array data.

Results: We developed a method named Co-Methylation with genomic CpG Background (CoMeBack) that estimates DNA co-methylation, defined as proximal CpG probes with correlated DNAm across individuals. CoMeBack outputs co-methylated regions (CMRs), spanning sets of array probes constructed based on all genomic CpG sites, including those not measured on the array, and without any phenotypic variable inputs. This approach can reduce the multiple-test correction burden, while enhancing the discovery and specificity of statistical associations. We constructed and validated CMRs in whole blood, using publicly available Illumina Infinium 450 K array data from over 5000 individuals. These CMRs were enriched for enhancer chromatin states, and binding site motifs for several transcription factors involved in blood physiology. We illustrated how CMR-based epigenome-wide association studies can improve discovery and reduce false positives for associations with chronological age.

Availability And Implementation: https://bitbucket.org/flopflip/comeback.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa049DOI Listing
May 2020

Genetic susceptibility to asthma increases the vulnerability to indoor air pollution.

Eur Respir J 2020 03 26;55(3). Epub 2020 Mar 26.

Dept of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital and South African Medical Research Council Unit on Child and Adolescent Health, University of Cape Town, Cape Town, South Africa.

Introduction: Indoor air pollution and maternal smoking during pregnancy are associated with respiratory symptoms in infants, but little is known about the direct association with lung function or interactions with genetic risk factors. We examined associations of exposure to indoor particulate matter with a 50% cut-off aerodynamic diameter of 10 µm (PM) and maternal smoking with infant lung function and the role of gene-environment interactions.

Methods: Data from the Drakenstein Child Health Study, a South African birth cohort, were analysed (n=270). Lung function was measured at 6 weeks and 1 year of age, and lower respiratory tract infection episodes were documented. We measured pre- and postnatal PM exposures using devices placed in homes, and prenatal tobacco smoke exposure using maternal urine cotinine levels. Genetic risk scores determined from associations with childhood-onset asthma in the UK Biobank were used to investigate effect modifications.

Results: Pre- and postnatal exposure to PM as well as maternal smoking during pregnancy were associated with reduced lung function at 6 weeks and 1 year as well as with lower respiratory tract infection in the first year. Due to a significant interaction between the genetic risk score and prenatal exposure to PM, infants carrying more asthma-related risk alleles were more susceptible to PM-associated reduced lung function (p=0.007). This interaction was stronger in infants with Black African ancestry (p=0.001) and nonexistent in children with mixed ancestry (p=0.876).

Conclusions: PM and maternal smoking exposures were associated with reduced lung function, with a higher susceptibility for infants with an adverse genetic predisposition for asthma that also depended on the infant's ancestry.
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http://dx.doi.org/10.1183/13993003.01831-2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931665PMC
March 2020

Epigenetic aging in children from a small-scale farming society in The Congo Basin: Associations with child growth and family conflict.

Dev Psychobiol 2020 03 13;62(2):138-153. Epub 2019 Nov 13.

Department of Human Behavior, Ecology and Culture, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

Developmental environments influence individuals' long-term health trajectories, and there is increasing emphasis on understanding the biological pathways through which this occurs. Epigenetic aging evaluates DNA methylation at a suite of distinct CpG sites in the genome, and epigenetic age acceleration (EAA) is linked to heightened chronic morbidity and mortality risks in adults. Consequently, EAA provides insights on trajectories of biological aging, which early life experiences may help shape. However, few studies have measured correlates of children's epigenetic aging, especially outside of the U.S. and Europe. In particular, little is known about how children's growth and development relate to EAA in ecologies in which energetic and pathogenic stressors are commonplace. We studied EAA from dried blood spots among Bondongo children (n = 54) residing in a small-scale, fisher-farmer society in a remote region of the Republic of the Congo. Here, infectious disease burdens and their resultant energy demands are high. Children who were heavier for height or taller for age, respectively, exhibited greater EAA, including intrinsic EAA, which is considered to measure EAA internal to cells. Furthermore, we found that children in families with more conflict between parents had greater intrinsic EAA. These results suggest that in contexts in which limited energy must be allocated to competing demands, more investment in growth may coincide with greater EAA, which parallels findings in European children who do not face similar energetic constraints. Our findings also indicate that associations between adverse family environments and greater intrinsic EAA were nonetheless observable but only after adjustment for covariates relevant to the energetically and immunologically demanding nature of the local ecology.
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http://dx.doi.org/10.1002/dev.21935DOI Listing
March 2020

Biological embedding of experience: A primer on epigenetics.

Proc Natl Acad Sci U S A 2020 09 17;117(38):23261-23269. Epub 2019 Oct 17.

Program in Child and Brain Development, CIFAR, MaRS Centre, Toronto, ON, M5G 1M1, Canada;

Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. Although extensive correlative data exist supporting the notion that epigenetic mechanisms such as DNA methylation underlie biological embedding, causal data are lacking. We describe specific epigenetic mechanisms and their potential roles in the biological embedding of experience. We also consider the nuanced relationships between the genome, the epigenome, and gene expression. Our ability to connect biological embedding to the epigenetic landscape in its complexity is challenging and complicated by the influence of multiple factors. These include cell type, age, the timing of experience, sex, and DNA sequence. Recent advances in molecular profiling and epigenome editing, combined with the use of comparative animal and human longitudinal studies, should enable this field to transition from correlative to causal analyses.
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http://dx.doi.org/10.1073/pnas.1820838116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519272PMC
September 2020

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

Proc Natl Acad Sci U S A 2020 09 14;117(38):23329-23335. Epub 2019 Oct 14.

Department of Psychiatry, Harvard Medical School-McLean Hospital, Belmont, MA 02478.

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset ( = 1,032), with performance assessed in a separate test dataset ( = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.
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http://dx.doi.org/10.1073/pnas.1820843116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519312PMC
September 2020

Airway epithelial cell isolation techniques affect DNA methylation profiles with consequences for analysis of asthma related perturbations to DNA methylation.

Sci Rep 2019 10 8;9(1):14409. Epub 2019 Oct 8.

Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

The airway epithelium forms the interface between the inhaled environment and the lung. The airway epithelium is dysfunctional in asthma and epigenetic mechanisms are considered a contributory factor. We hypothesised that the DNA methylation profiles of cultured primary airway epithelial cells (AECs) would differ between cells isolated from individuals with asthma (n = 17) versus those without asthma (n = 16). AECs were isolated from patients by two different isolation techniques; pronase digestion (9 non-asthmatic, 8 asthmatic) and bronchial brushings (7 non-asthmatic and 9 asthmatic). DNA methylation was assessed using an Illumina Infinium HumanMethylation450 BeadChip array. DNA methylation of AECs clustered by isolation technique and linear regression identified 111 CpG sites differentially methylated between isolation techniques in healthy individuals. As a consequence, the effect of asthmatic status on DNA methylation was assessed within AEC samples isolated using the same technique. In pronase isolated AECs, 15 DNA regions were differentially methylated between asthmatics and non-asthmatics. In bronchial brush isolated AECs, 849 differentially methylated DNA regions were identified with no overlap to pronase regions. In conclusion, regardless of cell isolation technique, differential DNA methylation was associated with asthmatic status in AECs, providing further evidence for aberrant DNA methylation as a signature of epithelial dysfunction in asthma.
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http://dx.doi.org/10.1038/s41598-019-50873-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783553PMC
October 2019

5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns.

Mutagenesis 2019 12;34(4):315-322

School of Public Health, Center for Environmental Research and Children's Health (CERCH), University of California, Berkeley, Berkeley, CA, USA.

DNA methylation has been widely studied for associations with exposures and health outcomes. Both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks that may function differently to impact gene expression; however, the most commonly used technology to assess methylation for population studies in blood use are the Illumina 450K and EPIC BeadChips, for which the traditional bisulfite conversion does not differentiate 5mC and 5hmC marks. We used a modified protocol originally developed by Stewart et al. to analyse oxidative bisulfite-converted and conventional bisulfite-converted DNA for the same subject in parallel by the EPIC chip, allowing us to isolate the two measures. We measured 5mC and 5hmC in cord blood of 41 newborn participants of the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort and investigated differential methylation of 5mC + 5hmC, isolated 5mC and isolated 5hmC with sex at birth as an example of a biological variable previously associated with DNA methylation. Results showed low levels of 5hmC throughout the epigenome in the cord blood samples in comparison to 5mC. The concordance of autosomal hits between 5mC + 5hmC and exclusive 5mC analyses were low (25%); however, overlap was larger with increased effect size difference. There were 43 autosomal cytosine nucleotide followed by a guanine nucleotide (CpG) sites where 5hmC was associated with sex, 21 of which were unique to 5hmC after adjustment for cell composition. 5hmC only accounts for a small portion of overall methylation in cord blood; however, it has the potential to impact interpretation of combined 5hmC + 5mC studies in cord blood, especially given that effect sizes of differential methylation analyses are often small. Several significant CpG sites were unique to 5hmC, suggesting some functions distinct from 5mC. More studies of genome-wide 5hmC in children are warranted.
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http://dx.doi.org/10.1093/mutage/gez023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922517PMC
December 2019

DNA methylation of HPA-axis genes and the onset of major depressive disorder in adolescent girls: a prospective analysis.

Transl Psychiatry 2019 10 3;9(1):245. Epub 2019 Oct 3.

Department of Psychology, Stanford University, Stanford, USA.

The stress response system is disrupted in individuals with major depressive disorder (MDD) as well as in those at elevated risk for developing MDD. We examined whether DNA methylation (DNAm) levels of CpG sites within HPA-axis genes predict the onset of MDD. Seventy-seven girls, approximately half (n = 37) of whom were at familial risk for MDD, were followed longitudinally. Saliva samples were taken in adolescence (M age = 13.06 years [SD = 1.52]) when participants had no current or past MDD diagnosis. Diagnostic interviews were administered approximately every 18 months until the first onset of MDD or early adulthood (M age of last follow-up = 19.23 years [SD = 2.69]). We quantified DNAm in saliva samples using the Illumina EPIC chip and examined CpG sites within six key HPA-axis genes (NR3C1, NR3C2, CRH, CRHR1, CRHR2, FKBP5) alongside 59 genotypes for tagging SNPs capturing cis genetic variability. DNAm levels within CpG sites in NR3C1, CRH, CRHR1, and CRHR2 were associated with risk for MDD across adolescence and young adulthood. To rule out the possibility that findings were merely due to the contribution of genetic variability, we re-analyzed the data controlling for cis genetic variation within these candidate genes. Importantly, methylation levels in these CpG sites continued to significantly predict the onset of MDD, suggesting that variation in the epigenome, independent of proximal genetic variants, prospectively predicts the onset of MDD. These findings suggest that variation in the HPA axis at the level of the methylome may predict the development of MDD.
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http://dx.doi.org/10.1038/s41398-019-0582-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776528PMC
October 2019

MRE11-RAD50-NBS1 promotes Fanconi Anemia R-loop suppression at transcription-replication conflicts.

Nat Commun 2019 09 19;10(1):4265. Epub 2019 Sep 19.

Terry Fox Laboratory, BC Cancer, Vancouver, V5Z 1L3, Canada.

Ectopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors including the MRE11-RAD50-NBS1 (MRN) complex. While MRN has been shown to promote R-loops at DNA double-strand breaks, we show that it suppresses R-loops and associated DNA damage at transcription-replication conflicts. This occurs through a non-nucleolytic function of MRE11 that is important for R-loop suppression by the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms at transcription-replication conflicts.
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http://dx.doi.org/10.1038/s41467-019-12271-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753070PMC
September 2019

Regulation of Skn7-dependent, oxidative stress-induced genes by the RNA polymerase II-CTD phosphatase, Fcp1, and Mediator kinase subunit, Cdk8, in yeast.

J Biol Chem 2019 11 10;294(44):16080-16094. Epub 2019 Sep 10.

Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada

Fcp1 is a protein phosphatase that facilitates transcription elongation and termination by dephosphorylating the C-terminal domain of RNA polymerase II. High-throughput genetic screening and gene expression profiling of mutants revealed a novel connection to Cdk8, the Mediator complex kinase subunit, and Skn7, a key transcription factor in the oxidative stress response pathway. Briefly, Skn7 was enriched as a regulator of genes whose mRNA levels were altered in and Δ mutants and was required for the suppression of mutant growth defects by loss of under oxidative stress conditions. Targeted analysis revealed that mutating decreased Skn7 mRNA and protein levels as well as its association with target gene promoters but paradoxically increased the mRNA levels of Skn7-dependent oxidative stress-induced genes ( and ) under basal and induced conditions. The latter was in part recapitulated via chemical inhibition of transcription in WT cells, suggesting that a combination of transcriptional and posttranscriptional effects underscored the increased mRNA levels of and observed in the mutant. Interestingly, loss of robustly normalized the mRNA levels of Skn7-dependent genes in the mutant background and also increased Skn7 protein levels by preventing its turnover. As such, our work suggested that loss of could overcome transcriptional and/or posttranscriptional alterations in the mutant through its regulatory effect on Skn7. Furthermore, our work also implicated and in the broader response to environmental stressors in yeast.
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http://dx.doi.org/10.1074/jbc.RA119.008515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827322PMC
November 2019

Reversal of epigenetic aging and immunosenescent trends in humans.

Aging Cell 2019 12 8;18(6):e13028. Epub 2019 Sep 8.

Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Epigenetic "clocks" can now surpass chronological age in accuracy for estimating biological age. Here, we use four such age estimators to show that epigenetic aging can be reversed in humans. Using a protocol intended to regenerate the thymus, we observed protective immunological changes, improved risk indices for many age-related diseases, and a mean epigenetic age approximately 1.5 years less than baseline after 1 year of treatment (-2.5-year change compared to no treatment at the end of the study). The rate of epigenetic aging reversal relative to chronological age accelerated from -1.6 year/year from 0-9 month to -6.5 year/year from 9-12 month. The GrimAge predictor of human morbidity and mortality showed a 2-year decrease in epigenetic vs. chronological age that persisted six months after discontinuing treatment. This is to our knowledge the first report of an increase, based on an epigenetic age estimator, in predicted human lifespan by means of a currently accessible aging intervention.
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http://dx.doi.org/10.1111/acel.13028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826138PMC
December 2019

Social Environment and Epigenetics.

Curr Top Behav Neurosci 2019 ;42:83-126

Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital, Vancouver, BC, Canada.

Our social environment, from the microscopic to the macro-social, affects us for the entirety of our lives. One integral line of research to examine how interpersonal and societal environments can get "under the skin" is through the lens of epigenetics. Epigenetic mechanisms are adaptations made to our genome in response to our environment which include tags placed on and removed from the DNA itself to how our DNA is packaged, affecting how our genes are read, transcribed, and interact. These tags are affected by social environments and can persist over time; this may aid us in responding to experiences and exposures, both the enriched and the disadvantageous. From memory formation to immune function, the experience-dependent plasticity of epigenetic modifications to micro- and macro-social environments may contribute to the process of learning from comfort, pain, and stress to better survive in whatever circumstances life has in store.
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http://dx.doi.org/10.1007/7854_2019_114DOI Listing
January 2020

Comprehensive genomic profiling of glioblastoma tumors, BTICs, and xenografts reveals stability and adaptation to growth environments.

Proc Natl Acad Sci U S A 2019 09 30;116(38):19098-19108. Epub 2019 Aug 30.

Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4S6;

Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined. We used massively parallel sequencing technology to decode the genomes and transcriptomes of BTICs and xenografts and their matched tumors in order to delineate the potential impacts of the distinct growth environments. Using data generated from whole-genome sequencing of 201 samples and RNA sequencing of 118 samples, we show that BTICs and xenografts resemble their parental tumor at the genomic level but differ at the mRNA expression and epigenomic levels, likely due to the different growth environment for each sample type. These findings suggest that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug screens, and can help control for biases introduced by cell-culture conditions and the microenvironment in mouse models. We also found that lack of expression in pretreated GBM is linked to hypermutation, which in turn contributes to increased genomic heterogeneity and requires new strategies for GBM treatment.
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http://dx.doi.org/10.1073/pnas.1813495116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754609PMC
September 2019

Prenatal exposure to traffic-related air pollution, the gestational epigenetic clock, and risk of early-life allergic sensitization.

J Allergy Clin Immunol 2019 12 27;144(6):1729-1731.e5. Epub 2019 Aug 27.

University of British Columbia, Vancouver, British Columbia, Canada; British Columbia Children's Hospital, Vancouver, British Columbia, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2019.07.047DOI Listing
December 2019

Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data.

Clin Epigenetics 2019 08 27;11(1):125. Epub 2019 Aug 27.

Department of Biochemistry and Medical Genetics, University of Manitoba, and Children's Hospital Research Institute of Manitoba, Winnipeg, Canada.

Background: Umbilical cord blood (UCB) is commonly used in epigenome-wide association studies of prenatal exposures. Accounting for cell type composition is critical in such studies as it reduces confounding due to the cell specificity of DNA methylation (DNAm). In the absence of cell sorting information, statistical methods can be applied to deconvolve heterogeneous cell mixtures. Among these methods, reference-based approaches leverage age-appropriate cell-specific DNAm profiles to estimate cellular composition. In UCB, four reference datasets comprising DNAm signatures profiled in purified cell populations have been published using the Illumina 450 K and EPIC arrays. These datasets are biologically and technically different, and currently, there is no consensus on how to best apply them. Here, we systematically evaluate and compare these datasets and provide recommendations for reference-based UCB deconvolution.

Results: We first evaluated the four reference datasets to ascertain both the purity of the samples and the potential cell cross-contamination. We filtered samples and combined datasets to obtain a joint UCB reference. We selected deconvolution libraries using two different approaches: automatic selection using the top differentially methylated probes from the function pickCompProbes in minfi and a standardized library selected using the IDOL (Identifying Optimal Libraries) iterative algorithm. We compared the performance of each reference separately and in combination, using the two approaches for reference library selection, and validated the results in an independent cohort (Generation R Study, n = 191) with matched Fluorescence-Activated Cell Sorting measured cell counts. Strict filtering and combination of the references significantly improved the accuracy and efficiency of cell type estimates. Ultimately, the IDOL library outperformed the library from the automatic selection method implemented in pickCompProbes.

Conclusion: These results have important implications for epigenetic studies in UCB as implementing this method will optimally reduce confounding due to cellular heterogeneity. This work provides guidelines for future reference-based UCB deconvolution and establishes a framework for combining reference datasets in other tissues.
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http://dx.doi.org/10.1186/s13148-019-0717-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712867PMC
August 2019
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