External Resources 

Relevant to Key Research Themes:


theme1

Social Determinants of Health & Wellbeing

Epigenetics and Wellbeing James D. Baird

  • Mapping Interventions that promote mental health in the general population: A scoping review of reviews. Enns et al. 2016
  • Obesity prevention and obesogenic behavior interventions in child care: A systematic review. Sisson et al. 2016
  • How do mindfulness-based cognitive therapy and mindfulness-based stress reduction improve mental health and wellbeing? A systematic review and meta-analysis of mediation studies. Gu et al. 2015
Psychosocial & Material Factors

Induction of Suppressor Cells and Increased Tumor Growth following Chronic Psychosocial Stress in Male Mice. Schmidt et al. 2016

Prenatal maternal stress and wheeze in children: novel insights into epigenetic regulation. Trump et al. 2016

Stress-induced hyperalgesia (SIH) as a consequence of emotional deprivation and psychosocial traumatization in childhood. Implications for the treatment of chronic pain. Egle et al. 2016

Human Epigenome & Chronic Disease

Experience-sensitive epigenetic mechanisms, developmental plasticity, and the biological embedding of chronic disease risk. Cunliffe, 2015

Epidemiologic evidence for association between adverse environmental exposures in early life and epigenetic variation: a potential link to disease susceptibility? Vaiserman, 2015

Developmental programming and epigenetics. Junien et al. 2011


theme2

Model Organisms
  • Mice age - Does the age of the mother predict offspring behaviour? Lerch et al. 2015
  • Bred to breed?! Implications of continuous mating on the emotional status of mouse offspring. Lerch et al. 2014
Embedding of Behaviour

Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Sunderman et al. 2012

Psychosocial Stress on the Epigenome

The epigenetic regulator Histone Deacetylase 1 promotes transcription of a core neurogenic programme in zebrafish embryos. Harrison et al. 2011


theme3

Epigenetic Impacts on Society
Social Theory

The role of social scientists in synthetic biology. Calvert and Martin, 2009

Public Policy

PubMed Resources Relating to Epigenetics

Maternal blood lead concentrations, DNA methylation of MEG3 DMR regulating the DLK1/MEG3 imprinted domain and early growth in a multiethnic cohort.

Environ Epigenet. 2016;2(1):

Authors: Nye MD, King KE, Darrah TH, Maguire R, Jima DD, Huang Z, Mendez MA, Fry RC, Jirtle RL, Murphy SK, Hoyo C

Abstract
Prenatal exposure to lead (Pb) is known to decrease fetal growth; but its effects on postnatal growth and mechanistic insights linking Pb to growth are not clearly defined. Genomically imprinted genes are powerful regulators of growth and energy utilization, and may be particularly vulnerable to environmental Pb exposure. Because imprinting is established early and maintained via DNA methylation, we hypothesized that prenatal Pb exposure alters DNA methylation of imprinted genes resulting in lower birth weight and rapid growth. Pb was measured by inductively coupled plasma mass spectrometry (ICP-MS) in peripheral blood of 321 women of the Newborn Epigenetic STudy (NEST) obtained at gestation ~12 weeks. Linear and logistic regression models were used to evaluate associations between maternal Pb levels, methylation of differentially methylated regions (DMRs) regulating H19, MEG3, PEG3, and PLAGL1, measured by pyrosequencing, birth weight, and weight-for-height z score gains between birth and age 1yr, ages 1-2yrs, and 2-3yrs. Children born to women with Pb levels in the upper tertile had higher methylation of the regulatory region of the MEG3 DMR imprinted domain (β= 1.57, se= 0.82, p= 0.06). Pb levels were also associated with lower birth weight (β= -0.41, se= 0.15, p= 0.01) and rapid gains in adiposity (OR= 12.32, 95%CI=1.25-121.30, p= 0.03) by age 2-3 years. These data provide early human evidence for Pb associations with hypermethylation at the MEG3 DMR regulatory region and rapid adiposity gain-a risk factor for childhood obesity and cardiometabolic diseases in adulthood.

PMID: 28123784 [PubMed - in process]

]]> Nye MD, King KE, Darrah TH, Maguire R, Jima DD, Huang Z, Mendez MA, Fry RC, Jirtle RL, Murphy SK, Hoyo C Environ Epigenet PubMed:28123784 https://www.ncbi.nlm.nih.gov/pubmed/28119717?dopt=Abstract Related Articles

The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Alleviates Salinity Stress in Cassava.

Front Plant Sci. 2016;7:2039

Authors: Patanun O, Ueda M, Itouga M, Kato Y, Utsumi Y, Matsui A, Tanaka M, Utsumi C, Sakakibara H, Yoshida M, Narangajavana J, Seki M

Abstract
Cassava (Manihot esculenta Crantz) demand has been rising because of its various applications. High salinity stress is a major environmental factor that interferes with normal plant growth and limits crop productivity. As well as genetic engineering to enhance stress tolerance, the use of small molecules is considered as an alternative methodology to modify plants with desired traits. The effectiveness of histone deacetylase (HDAC) inhibitors for increasing tolerance to salinity stress has recently been reported. Here we use the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), to enhance tolerance to high salinity in cassava. Immunoblotting analysis reveals that SAHA treatment induces strong hyper-acetylation of histones H3 and H4 in roots, suggesting that SAHA functions as the HDAC inhibitor in cassava. Consistent with increased tolerance to salt stress under SAHA treatment, reduced Na(+) content and increased K(+)/Na(+) ratio were detected in SAHA-treated plants. Transcriptome analysis to discover mechanisms underlying salinity stress tolerance mediated through SAHA treatment reveals that SAHA enhances the expression of 421 genes in roots under normal condition, and 745 genes at 2 h and 268 genes at 24 h under both SAHA and NaCl treatment. The mRNA expression of genes, involved in phytohormone [abscisic acid (ABA), jasmonic acid (JA), ethylene, and gibberellin] biosynthesis pathways, is up-regulated after high salinity treatment in SAHA-pretreated roots. Among them, an allene oxide cyclase (MeAOC4) involved in a crucial step of JA biosynthesis is strongly up-regulated by SAHA treatment under salinity stress conditions, implying that JA pathway might contribute to increasing salinity tolerance by SAHA treatment. Our results suggest that epigenetic manipulation might enhance tolerance to high salinity stress in cassava.

PMID: 28119717 [PubMed - in process]

]]> Patanun O, Ueda M, Itouga M, Kato Y, Utsumi Y, Matsui A, Tanaka M, Utsumi C, Sakakibara H, Yoshida M, Narangajavana J, Seki M Front Plant Sci PubMed:28119717 https://www.ncbi.nlm.nih.gov/pubmed/28033363?dopt=Abstract Related Articles

Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype.

PLoS One. 2016;11(12):e0168988

Authors: Gabriel D, Gordon LB, Djabali K

Abstract
Hutchinson-Gilford syndrome (HGPS, OMIM 176670, a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke, is caused by mutations in the LMNA gene. Lamins help maintain the shape and stability of the nuclear envelope in addition to regulating DNA replication, DNA transcription, proliferation and differentiation. The LMNA mutation results in the deletion of 50 amino acids from the carboxy-terminal region of prelamin A, producing the truncated, farnesylated protein progerin. The accumulation of progerin in HGPS nuclei causes numerous morphological and functional changes that lead to premature cellular senescence. Attempts to reverse this HGPS phenotype have identified rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), as a drug that is able to rescue the HGPS cellular phenotype by promoting autophagy and reducing progerin accumulation. Rapamycin is an obvious candidate for the treatment of HGPS disease but is difficult to utilize clinically. To further assess rapamycin's efficacy with regard to proteostasis, mitochondrial function and the degree of DNA damage, we tested temsirolimus, a rapamycin analog with a more favorable pharmacokinetic profile than rapamycin. We report that temsirolimus decreases progerin levels, increases proliferation, reduces misshapen nuclei, and partially ameliorates DNA damage, but does not improve proteasome activity or mitochondrial dysfunction. Our findings suggest that future therapeutic strategies should identify new drug combinations and treatment regimens that target all the dysfunctional hallmarks that characterize HGPS cells.

PMID: 28033363 [PubMed - indexed for MEDLINE]

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Gabriel D, Gordon LB, Djabali K PLoS One PubMed:28033363
https://www.ncbi.nlm.nih.gov/pubmed/28018572?dopt=Abstract Related Articles

Placental methylome analysis from a prospective autism study.

Mol Autism. 2016;7:51

Authors: Schroeder DI, Schmidt RJ, Crary-Dooley FK, Walker CK, Ozonoff S, Tancredi DJ, Hertz-Picciotto I, LaSalle JM

Abstract
BACKGROUND: Autism spectrum disorders (ASD) are increasingly prevalent neurodevelopmental disorders that are behaviorally diagnosed in early childhood. Most ASD cases likely arise from a complex mixture of genetic and environmental factors, an interface where the epigenetic marks of DNA methylation may be useful as risk biomarkers. The placenta is a potentially useful surrogate tissue characterized by a methylation pattern of partially methylated domains (PMDs) and highly methylated domains (HMDs) reflective of methylation patterns observed in the early embryo.
METHODS: In this study, we investigated human term placentas from the MARBLES (Markers of Autism Risk in Babies: Learning Early Signs) prospective study by whole genome bisulfite sequencing. We also examined the utility of PMD/HMDs in detecting methylation differences consistent with ASD diagnosis at age three.
RESULTS: We found that while human placental methylomes have highly reproducible PMD and HMD locations, there is a greater variation between individuals in methylation levels over PMDs than HMDs due to both sampling and individual variability. In a comparison of methylation differences in placental samples from 24 ASD and 23 typically developing (TD) children, a HMD containing a putative fetal brain enhancer near DLL1 was found to reach genome-wide significance and was validated for significantly higher methylation in ASD by pyrosequencing.
CONCLUSIONS: These results suggest that the placenta could be an informative surrogate tissue for predictive ASD biomarkers in high-risk families.

PMID: 28018572 [PubMed - in process]

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Schroeder DI, Schmidt RJ, Crary-Dooley FK, Walker CK, Ozonoff S, Tancredi DJ, Hertz-Picciotto I, LaSalle JM Mol Autism PubMed:28018572
https://www.ncbi.nlm.nih.gov/pubmed/27999621?dopt=Abstract Related Articles

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract.

Clin Epigenetics. 2016;8:133

Authors: Branchi V, Schaefer P, Semaan A, Kania A, Lingohr P, Kalff JC, Schäfer N, Kristiansen G, Dietrich D, Matthaei H

Abstract
BACKGROUND: Biliary tract carcinoma (BTC) is a fatal malignancy which aggressiveness contrasts sharply with its relatively mild and late clinical presentation. Novel molecular markers for early diagnosis and precise treatment are urgently needed. The purpose of this study was to evaluate the diagnostic and prognostic value of promoter hypermethylation of the SHOX2 and SEPT9 gene loci in BTC.
METHODS: Relative DNA methylation of SHOX2 and SEPT9 was quantified in tumor specimens and matched normal adjacent tissue (NAT) from 71 BTC patients, as well as in plasma samples from an independent prospective cohort of 20 cholangiocarcinoma patients and 100 control patients. Receiver operating characteristic (ROC) curve analyses were performed to probe the diagnostic ability of both methylation markers. DNA methylation was correlated to clinicopathological data and to overall survival.
RESULTS: SHOX2 methylation was significantly higher in tumor tissue than in NAT irrespective of tumor localization (p < 0.001) and correctly identified 71% of BTC specimens with 100% specificity (AUC = 0.918; 95% CI 0.865-0.971). SEPT9 hypermethylation was significantly more frequent in gallbladder carcinomas compared to cholangiocarcinomas (p = 0.01) and was associated with large primary tumors (p = 0.01) as well as age (p = 0.03). Cox proportional hazard analysis confirmed microscopic residual tumor at the surgical margin (R1-resection) as an independent prognostic factor, while SHOX2 and SEPT9 methylation showed no correlation with overall survival. Elevated DNA methylation levels were also found in plasma derived from cholangiocarcinoma patients. SHOX2 and SEPT9 methylation as a marker panel achieved a sensitivity of 45% and a specificity of 99% in differentiating between samples from patients with and without cholangiocarcinoma (AUC = 0.752; 95% CI 0.631-0.873).
CONCLUSIONS: SHOX2 and SEPT9 are frequently methylated in biliary tract cancers. Promoter hypermethylation of SHOX2 and SEPT9 may therefore serve as a minimally invasive biomarker supporting diagnosis finding and therapy monitoring in clinical specimens.

PMID: 27999621 [PubMed - indexed for MEDLINE]

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Branchi V, Schaefer P, Semaan A, Kania A, Lingohr P, Kalff JC, Schäfer N, Kristiansen G, Dietrich D, Matthaei H Clin Epigenetics PubMed:27999621
https://www.ncbi.nlm.nih.gov/pubmed/27980694?dopt=Abstract Related Articles

A methylation PCR method determines FMR1 activation ratios and differentiates premutation allele mosaicism in carrier siblings.

Clin Epigenetics. 2016;8:130

Authors: Hadd AG, Filipovic-Sadic S, Zhou L, Williams A, Latham GJ, Berry-Kravis E, Hall DA

Abstract
BACKGROUND: Epigenetic modifications of the fragile X mental retardation 1 (FMR1) gene locus may impact the risk for reproductive and neurological disorders associated with expanded trinucleotide repeats and methylation status in the 5' untranslated region. FMR1 methylation is commonly assessed by Southern blot (SB) analysis, yet this method suffers a cumbersome workflow and relatively poor sizing resolution especially for premutation allele characteristic for fragile X-associated disorders. In this study, a methylation PCR (mPCR) assay was used to evaluate correlations among genotype, epitype, and phenotype in fragile X premutation (PM) carrier women in order to advance the understanding of the association between molecular determinants and the presence of fragile X-associated tremor and ataxia (FXTAS).
RESULTS: Activation ratios (ARs) in 39 PM women were determined by mPCR and compared with SB analysis. ARs were distributed across a range of values including five samples with <20% AR and six with >80% AR. The two methods were correlated (R(2) of 0.87 and F test of <0.001), indicating that mPCR can measure AR in agreement with established assays. However, mPCR was unique in identifying novel and distinct patterns of methylation mosaicism in premutation carrier women, including seven sibling pairs that were assessed using FXTAS clinical rating scales. Of note, four of six pairs with defined age of onset for neurological signs showed ARs consistent with skewed activation of the pathogenic expanded allele. One subject with severe FXTAS had a mosaic full mutation allele identified using mPCR but not detected by SB analysis.
CONCLUSIONS: We utilized a repeatable and streamlined methodology to characterize FMR1 inactivation in premutation carrier women. The method was concordant with SB analysis and provided higher resolution information on allele and methylation mosaicism. This approach can facilitate the characterization of epigenetic factors influencing fragile X phenotypes in larger cohort studies that can advance understanding and treatment of fragile X-associated disorders.

PMID: 27980694 [PubMed - indexed for MEDLINE]

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Hadd AG, Filipovic-Sadic S, Zhou L, Williams A, Latham GJ, Berry-Kravis E, Hall DA Clin Epigenetics PubMed:27980694
https://www.ncbi.nlm.nih.gov/pubmed/27933088?dopt=Abstract Related Articles

Comparison of Ionomic and Metabolites Response under Alkali Stress in Old and Young Leaves of Cotton (Gossypium hirsutum L.) Seedlings.

Front Plant Sci. 2016;7:1785

Authors: Guo R, Shi L, Yang C, Yan C, Zhong X, Liu Q, Xia X, Li H

Abstract
Soil salinization is an important agriculture-related environmental problem. Alkali stress and salt stress strongly influence the metabolic balance in plants. Salt and alkali stresses exert varied effects on old and young tissues, which display different adaptive strategies. In this study, we used cotton (Gossypium hirsutum L.) plants as experimental material to investigate whether alkali stress induces ionic and metabolism changes in old and young leaves of cotton plants exposed to alkali stress. Results showed that alkali stress exerted a considerably stronger growth inhibition on old leaves than on young leaves. Under alkali stress, young leaves can maintain low Na and high K contents and retain relatively stable tricarboxylic acid cycle, resulting in greater accumulation of photosynthetic metabolites. In terms of metabolic response, the young and old leaves clearly displayed different mechanisms of osmotic regulation. The amounts of inositol and mannose significantly increased in both old and young leaves of cotton exposed to alkali stress, and the extent of increase was higher in young leaves than in old leaves. In old leaves, synthesis of amino acids, such as GABA, valine, and serine, was dramatically enhanced, and this phenomenon is favorable for osmotic adjustment and membrane stability. Organs at different developmental stages possibly display different mechanisms of metabolic regulation under stress condition. Thus, we propose that future investigations on alkali stress should use more organs obtained at different developmental stages.

PMID: 27933088 [PubMed - in process]

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Guo R, Shi L, Yang C, Yan C, Zhong X, Liu Q, Xia X, Li H Front Plant Sci PubMed:27933088
https://www.ncbi.nlm.nih.gov/pubmed/27924164?dopt=Abstract Related Articles

Smoking-associated DNA methylation markers predict lung cancer incidence.

Clin Epigenetics. 2016;8:127

Authors: Zhang Y, Elgizouli M, Schöttker B, Holleczek B, Nieters A, Brenner H

Abstract
BACKGROUND: Newly established blood DNA methylation markers that are strongly associated with smoking might open new avenues for lung cancer (LC) screening. We aimed to assess the performance of the top hits from previous epigenome-wide association studies in prediction of LC incidence. In a prospective nested case-control study, DNA methylation at AHRR (cg05575921), 6p21.33 (cg06126421), and F2RL3 (cg03636183) were measured by pyrosequencing in baseline whole blood samples of 143 incident LC cases identified during 11 years of follow-up and 457 age- and sex-matched controls without diagnosis of LC until the end of follow-up. The individual and joint associations of the 3 markers with LC risk were estimated by logistic regression, adjusted for potential confounders including smoking status and cigarette pack-years. The predictive performance was evaluated for both the individual markers and their combinations derived from multiple algorithms.
RESULTS: Pronounced demethylation of all 3 markers was observed at baseline among cases compared to controls. Risk of developing LC increased with decreasing DNA methylation levels, with adjusted ORs (95% CI) of 15.86 (4.18-60.17), 8.12 (2.69-4.48), and 10.55 (3.44-32.31), respectively, for participants in the lowest quartile of AHRR, 6p21.33, and F2RL3 compared to participants in the highest 2 quartiles of each site among controls. The individual 3 markers exhibited similar accuracy in predicting LC incidence, with AUCs ranging from 0.79 to 0.81. Combination of the 3 markers did not improve the predictive performance (AUC = 0.80). The individual markers or their combination outperformed self-reported smoking exposure particularly in light smokers. No variation in risk prediction was identified with respect to age, follow-up time, and histological subtypes.
CONCLUSIONS: AHRR, 6p21.33, and F2RL3 methylation in blood DNA are predictive for LC development, which might be useful for identification of risk groups for further specific screening, such as CT examination.

PMID: 27924164 [PubMed - indexed for MEDLINE]

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Zhang Y, Elgizouli M, Schöttker B, Holleczek B, Nieters A, Brenner H Clin Epigenetics PubMed:27924164
https://www.ncbi.nlm.nih.gov/pubmed/27920589?dopt=Abstract Related Articles

DNA Methylation of Regulatory Regions of Imprinted Genes at Birth and Its Relation to Infant Temperament.

Genet Epigenet. 2016;8:59-67

Authors: Fuemmeler BF, Lee CT, Soubry A, Iversen ES, Huang Z, Murtha AP, Schildkraut JM, Jirtle RL, Murphy SK, Hoyo C

Abstract
BACKGROUND: DNA methylation of the differentially methylated regions (DMRs) of imprinted genes is relevant to neurodevelopment.
METHODS: DNA methylation status of the DMRs of nine imprinted genes in umbilical cord blood leukocytes was analyzed in relation to infant behaviors and temperament (n = 158).
RESULTS: MEG3 DMR levels were positively associated with internalizing (β = 0.15, P = 0.044) and surgency (β = 0.19, P = 0.018) behaviors, after adjusting for birth weight, gender, gestational age at birth, maternal age at delivery, race/ethnicity, education level, smoking status, parity, and a history of anxiety or depression. Higher methylation levels at the intergenic MEG3-IG methylation regions were associated with surgency (β = 0.28, P = 0.0003) and PEG3 was positively related to externalizing (β = 0.20, P = 0.01) and negative affectivity (β = 0.18, P = 0.02).
CONCLUSION: While the small sample size limits inference, these pilot data support gene-specific associations between epigenetic differences in regulatory regions of imprinted domains at birth and later infant temperament.

PMID: 27920589 [PubMed - in process]

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Fuemmeler BF, Lee CT, Soubry A, Iversen ES, Huang Z, Murtha AP, Schildkraut JM, Jirtle RL, Murphy SK, Hoyo C Genet Epigenet PubMed:27920589
https://www.ncbi.nlm.nih.gov/pubmed/27904521?dopt=Abstract Related Articles

Epigenetic modifications in adipose tissue - relation to obesity and diabetes.

Arch Med Sci. 2016 Dec 01;12(6):1293-1301

Authors: Kasinska MA, Drzewoski J, Sliwinska A

Abstract
The growing number of people suffering from obesity and type 2 diabetes mellitus (T2DM) is a global health problem that results in increased mortality from their complications, mainly cardiovascular diseases. Although the relationship between obesity and T2DM is well established, the common molecular pathomechanisms are still under investigation. Recently, it has been suggested that epigenetic modifications may be involved in both obesity and T2DM development. Epigenetics plays a pivotal role in the regulation of gene expression by the reversible modifications of chromatin structure without any changes in DNA sequence. Epigenetic modifications include DNA methylation, posttranslational histone modifications and miRNA interference. Therefore, the aim of this article is to discuss the current knowledge on epigenetic modifications in adipose tissue and their association with obesity and T2DM.

PMID: 27904521 [PubMed]

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Kasinska MA, Drzewoski J, Sliwinska A Arch Med Sci PubMed:27904521