Publications by authors named "J T Goodrich"

610 Publications

Considering Environmental Exposures to Per- and Polyfluoroalkyl Substances (PFAS) as Risk Factors for Hypertensive Disorders of Pregnancy.

Environ Res 2021 Apr 3:111113. Epub 2021 Apr 3.

Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109. Electronic address:

Hypertensive disorders of pregnancy (HDP), including preeclampsia and gestational hypertension, lead to significant maternal morbidity and in some cases, maternal mortality. Environmental toxicants, especially those that disrupt normal placental and endothelial function, are emerging as potential risk factors for HDP. Per- and polyfluoroalkyl substances (PFAS) are a large group of ubiquitous chemicals found in consumer products, the environment, and increasingly in drinking water. PFAS have been associated with a multitude of adverse health effects, including dyslipidemia, hypertension, and more recently, HDP. In this review, we present epidemiological and mechanistic evidence for the link between PFAS and HDP and recommend next steps for research and prevention efforts. To date, epidemiological studies have assessed associations between only ten of the thousands of PFAS and HDP. Positive associations between six PFAS (PFOA, perfluorooctanoic acid; PFOS, perfluorooctane sulfonic acid; PFHxS, perfluorohexane sulfonic acid; PFHpA, perfluoroheptanoic acid; PFBS, perfluorobutanesulfonic acid; and PFNA, perfluoronanoic acid) and risk for HDP have been reported in some, but not all, studies. PFAS disrupt placental and immune function, cause oxidative stress, and disrupt lipid metabolism. These physiological disruptions may be mechanisms through which PFAS can lead to HDP. Overall, limited epidemiological evidence and plausible mechanisms support PFAS as risk factors for HDP. More research is needed in diverse, well-powered cohorts that assess exposures to as many PFAS as possible. Such research should consider not only individual PFAS but also the totality of exposures to PFAS and other environmental chemicals. Pregnant women may be a group that is vulnerable to PFAS exposure, and as such HDP risk should be considered by policymakers setting PFAS exposure limits. In the interim, medical and public health professionals in regions with PFAS contamination could provide short-term solutions in the form of patient-level prevention, increased monitoring, and early intervention for HDP.
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http://dx.doi.org/10.1016/j.envres.2021.111113DOI Listing
April 2021

Exposure to Phenols, Phthalates, and Parabens and Development of Metabolic Syndrome Among Mexican Women in Midlife.

Front Public Health 2021 26;9:620769. Epub 2021 Feb 26.

Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, United States.

Evidence suggests exposure to endocrine-disrupting chemicals (EDCs) can influence Metabolic Syndrome (MetS) risk in adults, but it is unclear if EDCs impact women during midlife. We examined if EDCs measured in adult women were predictive of MetS and its components 9 years later. We measured urinary phthalate metabolites, phenols, and parabens collected in 2008 among 73 females from the ELEMENT study. MetS and its components (Abdominal Obesity, Hypertriglyceridemia, Cholesterolemia, Hypertension, and Hyperglycemia) were assessed in 2017. We regressed log-transformed EDC concentrations on MetS and MetS components using logistic regression, adjusting for age and physical activity. At follow-up, the mean (SD) age was 46.6 (6.3) years; the prevalence of MetS was 34.3%. Sum of dibutyl phthalate metabolites (ΣDBP), monobenzyl phthalate (MBzP), and monoethyl phthalate (MEP) were associated with an increased odds of hypertriglyceridemia. 2,5-dichlorophenol (2,5 DCP) and 2,4-dichlorophenol (2,4 DCP) were associated with increased odds of hypertriglyceridemia. The odds of hypertension were 4.18 (95% CI: 0.98, 17.7, < 0.10) and 3.77 (95% CI: 0.76, 18.62, < 0.10) times higher for every IQR increase in MCOP and propyl paraben, respectively. The odds of hyperglycemia were 0.46 (95% CI: 0.18, 1.17 < 0.10) times lower for every IQR increase in the sum of di-2-ethylhexyl phthalate metabolites (ΣDEHP), and the odds of abdominal obesity were 0.70 (95% CI: 0.40, 1.21, < 0.10) lower for every IQR increase in the concentration of triclosan. We found EDCs measured in 2008 were marginally predictive of hypertriglyceridemia and hypertension 9 years later. Results suggest that lower exposure to certain toxicants was related to lower markers of metabolic risk among midlife women.
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http://dx.doi.org/10.3389/fpubh.2021.620769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952420PMC
February 2021

MR Elastography demonstrates reduced white matter shear stiffness in early-onset hydrocephalus.

Neuroimage Clin 2021 Feb 2;30:102579. Epub 2021 Feb 2.

Montefiore Medical Center, Department of Neurosurgery, Bronx, NY, USA.

Introduction: Hydrocephalus that develops early in life is often accompanied by developmental delays, headaches and other neurological deficits, which may be associated with changes in brain shear stiffness. However, noninvasive approaches to measuring stiffness are limited. Magnetic Resonance Elastography (MRE) of the brain is a relatively new noninvasive imaging method that provides quantitative measures of brain tissue stiffness. Herein, we aimed to use MRE to assess brain stiffness in hydrocephalus patients compared to healthy controls, and to assess its associations with ventricular size, as well as demographic, shunt-related and clinical outcome measures.

Methods: MRE was collected at two imaging sites in 39 hydrocephalus patients and 33 healthy controls, along with demographic, shunt-related, and clinical outcome measures including headache and quality of life indices. Brain stiffness was quantified for whole brain, global white matter (WM), and lobar WM stiffness. Group differences in brain stiffness between patients and controls were compared using two-sample t-tests and multivariable linear regression to adjust for age, sex, and ventricular volume. Among patients, multivariable linear or logistic regression was used to assess which factors (age, sex, ventricular volume, age at first shunt, number of shunt revisions) were associated with brain stiffness and whether brain stiffness predicts clinical outcomes (quality of life, headache and depression).

Results: Brain stiffness was significantly reduced in patients compared to controls, both unadjusted (p ≤ 0.002) and adjusted (p ≤ 0.03) for covariates. Among hydrocephalic patients, lower stiffness was associated with older age in temporal and parietal WM and whole brain (WB) (beta (SE): -7.6 (2.5), p = 0.004; -9.5 (2.2), p = 0.0002; -3.7 (1.8), p = 0.046), being female in global and frontal WM and WB (beta (SE): -75.6 (25.5), p = 0.01; -66.0 (32.4), p = 0.05; -73.2 (25.3), p = 0.01), larger ventricular volume in global, and occipital WM (beta (SE): -11.5 (3.4), p = 0.002; -18.9 (5.4), p = 0.0014). Lower brain stiffness also predicted worse quality of life and a higher likelihood of depression, controlling for all other factors.

Conclusions: Brain stiffness is reduced in hydrocephalus patients compared to healthy controls, and is associated with clinically-relevant functional outcome measures. MRE may emerge as a clinically-relevant biomarker to assess the neuropathological effects of hydrocephalus and shunting, and may be useful in evaluating the effects of therapeutic alternatives, or as a supplement, of shunting.
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http://dx.doi.org/10.1016/j.nicl.2021.102579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905205PMC
February 2021

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.

Genome Biol Evol 2021 Feb;13(2)

Department of Anthropology, University of California, Los Angeles.

High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.
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http://dx.doi.org/10.1093/gbe/evaa239DOI Listing
February 2021

Early Life Exposure to Aflatoxin B1 in Rats: Alterations in Lipids, Hormones, and DNA Methylation among the Offspring.

Int J Environ Res Public Health 2021 01 12;18(2). Epub 2021 Jan 12.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.

Aflatoxins are toxic compounds produced by molds of the species that contaminate food primarily in tropical countries. The most toxic aflatoxin, aflatoxin B1 (AFB1), is a major cause of hepatocellular carcinoma (HCC) in these countries. In sub-Saharan Africa, aflatoxin contamination is common, and perinatal AFB1 exposure has been linked to the early onset of HCC. Epigenetic programming, including changes to DNA methylation, is one mechanism by which early life exposures can lead to adult disease. This study aims to elucidate whether perinatal AFB1 exposure alters markers of offspring health including weight, lipid, and hormone profiles as well as epigenetic regulation that may later influence cancer risk. Pregnant rats were exposed to two doses of AFB1 (low 0.5 and high 5 mg/kg) before conception, throughout pregnancy, and while weaning and compared to an unexposed group. Offspring from each group were followed to 3 weeks or 3 months of age, and their blood and liver samples were collected. Body weights and lipids were assessed at 3 weeks and 3 months while reproductive, gonadotropic, and thyroid hormones were assessed at 3 months. Prenatal AFB1 (high dose) exposure resulted in significant 16.3%, 31.6%, and 7.5% decreases in weight of the offspring at birth, 3 weeks, and 3 months, respectively. Both doses of exposure altered lipid and hormone profiles. Pyrosequencing was used to quantify percent DNA methylation at tumor suppressor gene and growth-regulator in DNA from liver and blood. Results were compared between the control and AFB1 exposure groups in 3-week liver samples and 3-week and 3-month blood samples. Relative to controls, DNA methylation in both low- and high-dose exposed rats was significantly decreased in liver samples and increased in the blood ( < 0.05 in linear mixed models). methylation was higher in the liver from low- and high-exposed rats and decreased in 3-month blood samples from the high exposure group ( < 0.05). Further research is warranted to determine whether such hormone, lipid, and epigenetic alterations from AFB1 exposure early in life play a role in the development of early-onset HCC.
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http://dx.doi.org/10.3390/ijerph18020589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828191PMC
January 2021

Maternal environmental exposure to bisphenols and epigenome-wide DNA methylation in infant cord blood.

Environ Epigenet 2020 23;6(1):dvaa021. Epub 2020 Dec 23.

Department of Environmental Health Sciences, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI 48109, USA.

Maternal prenatal exposures, including bisphenol A (BPA), are associated with offspring's risk of disease later in life. Alterations in DNA methylation may be a mechanism through which altered prenatal conditions (e.g. maternal exposure to environmental toxicants) elicit this disease risk. In the Michigan Mother and Infant Pairs Cohort, maternal first-trimester urinary BPA, bisphenol F, and bisphenol S concentrations were tested for association with DNA methylation patterns in infant umbilical cord blood leukocytes ( = 69). We used the Illumina Infinium MethylationEPIC BeadChip to quantitatively evaluate DNA methylation across the epigenome; 822 020 probes passed pre-processing and quality checks. Single-site DNA methylation and bisphenol models were adjusted for infant sex, estimated cell-type proportions (determined using cell-type estimation algorithm), and batch as covariates. Thirty-eight CpG sites [false discovery rate (FDR) <0.05] were significantly associated with maternal BPA exposure. Increasing BPA concentrations were associated with lower DNA methylation at 87% of significant sites. BPA exposure associated DNA methylation sites were enriched for 38 pathways significant at FDR <0.05. The pathway or gene-set with the greatest odds of enrichment for differential methylation (FDR <0.05) was type I interferon receptor binding. This study provides a novel understanding of fetal response to maternal bisphenol exposure through epigenetic change.
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http://dx.doi.org/10.1093/eep/dvaa021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757124PMC
December 2020

Emergency response to stormwater contamination: A framework for containment and treatment.

J Environ Manage 2021 Feb 23;280:111838. Epub 2020 Dec 23.

Homeland Security Materials Management Division, USEPA Office of Research & Development, Cincinnati, OH, USA.

This paper presents a Stormwater Emergency Response Framework (SERF) for use in the containment and treatment of stormwater runoff following a hazardous material release. The framework consists of four high level process steps and a decision tree. These resources are intended to assist stormwater managers in fulfilling their emergency response responsibilities within the United States' National Incident Management System. Robust hydraulic and watershed modeling may take weeks to months to develop for a contaminated site, whereas decisions made in the initial hours can have a significant impact on limiting contamination spread. Many web resources are publicly available to assist responders in visualizing stormwater runoff flow paths. A case study provided in this paper also demonstrates how simple calculations may be utilized to estimate peak flows and storage volumes necessary to respond to precipitation events immediately. These calculations are useful for decision makers' allocation of containment and treatment resources within the impacted area. This includes where to deploy available resources to minimize contamination risks to downstream communities and where supplemental resources from outside partners are urgently needed.
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http://dx.doi.org/10.1016/j.jenvman.2020.111838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006087PMC
February 2021

Integrative Analysis of Gene-Specific DNA Methylation and Untargeted Metabolomics Data from the ELEMENT Cohort.

Epigenet Insights 2020 10;13:2516865720977888. Epub 2020 Dec 10.

Deptartment of Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA.

Epigenetic modifications, such as DNA methylation, influence gene expression and cardiometabolic phenotypes that are manifest in developmental periods in later life, including adolescence. Untargeted metabolomics analysis provide a comprehensive snapshot of physiological processes and metabolism and have been related to DNA methylation in adults, offering insights into the regulatory networks that influence cellular processes. We analyzed the cross-sectional correlation of blood leukocyte DNA methylation with 3758 serum metabolite features (574 of which are identifiable) in 238 children (ages 8-14 years) from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study. Associations between these features and percent DNA methylation in adolescent blood leukocytes at LINE-1 repetitive elements and genes that regulate early life growth () were assessed by mixed effects models, adjusting for sex, age, and puberty status. After false discovery rate correction (FDR < 0.05), 76 metabolites were significantly associated with LINE-1 DNA methylation, 27 with , 103 with , and 4 with . The ten identifiable metabolites included dicarboxylic fatty acids (five associated with LINE-1 or methylation at < 0.05) and 1-octadecanoyl-rac-glycerol ( < 0.0001 for association with and = 0.04 for association with LINE-1). We then assessed the association between these ten known metabolites and adiposity 3 years later. Two metabolites, dicarboxylic fatty acid 17:3 and 5-oxo-7-octenoic acid, were inversely associated with measures of adiposity ( < .05) assessed approximately 3 years later in adolescence. In stratified analyses, sex-specific and puberty-stage specific (Tanner stage = 2 to 5 vs Tanner stage = 1) associations were observed. Most notably, hundreds of statistically significant associations were observed between and LINE-1 DNA methylation and metabolites among children who had initiated puberty. Understanding relationships between subclinical molecular biomarkers (DNA methylation and metabolites) may increase our understanding of genes and biological pathways contributing to metabolic changes that underlie the development of adiposity during adolescence.
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http://dx.doi.org/10.1177/2516865720977888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734565PMC
December 2020

Maternal lipodome across pregnancy is associated with the neonatal DNA methylome.

Epigenomics 2020 12 8;12(23):2077-2092. Epub 2020 Dec 8.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.

To classify the association between the maternal lipidome and DNA methylation in cord blood leukocytes. Untargeted lipidomics was performed on first trimester maternal plasma (M1) and delivery maternal plasma (M3) in 100 mothers from the Michigan Mother-Infant Pairs cohort. Cord blood leukocyte DNA methylation was profiled using the Infinium EPIC bead array and empirical Bayes modeling identified differential DNA methylation related to maternal lipid groups. M3-saturated lysophosphatidylcholine was associated with 45 differentially methylated loci and M3-saturated lysophosphatidylethanolamine was associated with 18 differentially methylated loci. Biological pathways enriched among differentially methylated loci by M3 saturated lysophosphatidylcholines were related to cell proliferation and growth. The maternal lipidome may be influential in establishing the infant epigenome.
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http://dx.doi.org/10.2217/epi-2020-0234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857356PMC
December 2020

Association of Maternal-Neonatal Steroids With Early Pregnancy Endocrine Disrupting Chemicals and Pregnancy Outcomes.

J Clin Endocrinol Metab 2021 Mar;106(3):665-687

Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.

Context: Steroids play an important role in fetal development and parturition. Gestational exposures to endocrine-disrupting chemicals (EDCs) affect steroidal milieu and pregnancy outcomes, raising the possibility of steroids serving as biomarkers. Most studies have not addressed the impact of EDC mixtures, which are reflective of real life scenarios.

Objective: Assess the association of maternal and neonatal steroids with pregnancy outcomes and early pregnancy EDC levels.

Design: Prospective analysis of mother-infant dyads.

Setting: University hospital.

Participants: 121 mother-infant dyads.

Main Outcome Measures: The associations of maternal and neonatal steroidal hormones from 121 dyads with pregnancy outcomes, the associations of first trimester EDCs individually and as mixtures with maternal and neonatal steroids in a subset of 56 dyads and the influence of body mass index (BMI), age, and offspring sex in modulating the EDC associations with steroids were determined.

Results: Steroid-specific positive or negative associations with pregnancy measures were evident; many maternal first trimester EDCs were negatively associated with estrogens and positively with androgen/estrogen ratios; EDC-steroid associations were influenced by maternal age, pre-pregnancy BMI, and fetal sex; and EDCs individually and as mixtures showed direct and inverse fetal sex-dependent associations with maternal and neonatal steroids.

Conclusions: This proof-of-concept study indicates association of steroids with pregnancy outcomes depending on maternal age, prepregnancy BMI, and fetal sex, with the effects of EDCs differing when considered individually or as mixtures. These findings suggest that steroidal hormonal measures have potential to serve as biomarkers of impact of EDC exposures and pregnancy outcome.
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http://dx.doi.org/10.1210/clinem/dgaa909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947779PMC
March 2021

Large differences in CO emissions from two dairy farms on a drained peatland driven by contrasting respiration rates during seasonal dry conditions.

Sci Total Environ 2021 Mar 7;760:143410. Epub 2020 Nov 7.

School of Science, Environmental Research Institute, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand.

Drained peatlands are major sources of CO to the atmosphere, yet the effects of land management and hydrological extremes have been little-studied at spatial scales relevant to agricultural enterprises. We measured fluxes of CO using the eddy covariance (EC) technique at two adjacent dairy farms on a drained peatland in Aotearoa New Zealand with remaining peat depths 5.5-8 m. One site (SD) had shallow surface drains and mean water table depth (WTD) -657 mm, while the other site (BD) had deep field border drains and mean WTD -838 mm. Net ecosystem CO production (NEP) was similar at the two sites when the soils were moist but diverged during late-summer drying, with site BD having 4.56 t C ha greater CO emission than site SD over the four-month dry period. Soil drying reduced gross primary production (GPP) at both sites, while ecosystem respiration (ER) was reduced at site SD but not at site BD. The low dry season respiration rates at site SD contributed to near-zero annual NEP, while higher respiration rates at site BD led to annual CO loss of -4.95 ± 0.59 t C ha yr. Accounting for other imports and exports of carbon, annual net ecosystem carbon balances were -2.23 and -8.47 t C ha yr at sites SD and BD, respectively. It is likely that the contrasting dry season respiration rates resulted from differences in soil physical properties affecting soil moisture vertical redistribution and availability to plants and microbes rather than from the relatively small differences in WTD. These differences could be caused by soil physical disturbances during pasture renewal or paddock recontouring, or time since initial drainage. Therefore, improved soil management might provide practical mitigation against excessive CO emissions during dry conditions, including droughts.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143410DOI Listing
March 2021

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.

Genome Biol Evol 2021 Feb;13(2)

Department of Anthropology, University of California, Los Angeles.

High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.
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http://dx.doi.org/10.1093/gbe/evaa239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859850PMC
February 2021

Tissue and sex-specific programming of DNA methylation by perinatal lead exposure: implications for environmental epigenetics studies.

Epigenetics 2020 Nov 8:1-21. Epub 2020 Nov 8.

Environmental Health Sciences, University of Michigan School of Public Health , Ann Arbor, MI, USA.

Early developmental environment can influence long-term health through reprogramming of the epigenome. Human environmental epigenetics studies rely on surrogate tissues, such as blood, to assess the effects of environment on disease-relevant but inaccessible target tissues. However, the extent to which environment-induced epigenetic changes are conserved between these tissues is unclear. A better understanding of this conservation is imperative for effective design and interpretation of human environmental epigenetics studies. The Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription (TaRGET II) consortium was established by the National Institute of Environmental Health Sciences to address the utility of surrogate tissues as proxies for toxicant-induced epigenetic changes in target tissues. We and others have recently reported that perinatal exposure to lead (Pb) is associated with adverse metabolic outcomes. Here, we investigated the sex-specific effects of perinatal exposure to a human environmentally relevant level of Pb on DNA methylation in paired liver and blood samples from adult mice using enhanced reduced-representation bisulphite sequencing. Although Pb exposure ceased at 3 weeks of age, we observed thousands of sex-specific differentially methylated cytosines in the blood and liver of Pb-exposed animals at 5 months of age, including 44 genomically imprinted loci. We observed significant tissue overlap in the genes mapping to differentially methylated cytosines. A small but significant subset of Pb-altered genes exhibit basal sex differences in gene expression in the mouse liver. Collectively, these data identify potential molecular targets for Pb-induced metabolic diseases, and inform the design of more robust human environmental epigenomics studies.
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http://dx.doi.org/10.1080/15592294.2020.1841872DOI Listing
November 2020

Adolescent sleep timing and dietary patterns in relation to DNA methylation of core circadian genes: a pilot study of Mexican youth.

Epigenetics 2020 Oct 4:1-14. Epub 2020 Oct 4.

Department of Environmental Health Sciences, University of Michigan School of Public Health , Ann Arbor, MI, USA.

Mistimed sleep/wake and eating patterns put shift workers at increased risk for cardiometabolic disease, and epigenetic modification of circadian genes has been proposed as a mechanism. Although not as extreme as shift workers, adolescents often have delayed sleep timing and irregular eating patterns. The aim was to assess whether sleep midpoints - median of bed and wake time - and dietary patterns in adolescents were associated with DNA methylation of circadian genes. The study population included 142 Mexican youth (average age of 14.0 (SD = 2.0) years, 49% male). Average sleep midpoint over weekdays was estimated with actigraphy. Diet was assessed with a semi-quantitative food frequency questionnaire, and three dietary patterns were derived from principal component analysis, a pattern, a pattern, and an pattern. DNA methylation was quantified in blood leukocytes with the Infinium MethylationEPIC BeadChip, and data from 548 CpG sites within 12 circadian genes were examined. Linear regression analyses, adjusted for sex, age, and % monocytes, showed that later sleep timing was associated with higher DNA methylation of several circadian genes, notably with , and . Each of the dietary patterns examined was also related to circadian gene DNA methylation, but the pattern ('breakfast' pattern) had the clearest evidence of relationships with circadian genes, with inverse associations (lower DNA methylation) across all 12 genes. Findings suggest that timing-related sleep and eating behaviours among adolescents could result in epigenetic modification of clock genes.
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http://dx.doi.org/10.1080/15592294.2020.1827719DOI Listing
October 2020

Single molecule studies reveal that p53 tetramers dynamically bind response elements containing one or two half sites.

Sci Rep 2020 09 30;10(1):16176. Epub 2020 Sep 30.

Department of Biochemistry, University of Colorado Boulder, 596 UCB, Boulder, CO, 80309, USA.

The tumor suppressor protein p53 is critical for cell fate decisions, including apoptosis, senescence, and cell cycle arrest. p53 is a tetrameric transcription factor that binds DNA response elements to regulate transcription of target genes. p53 response elements consist of two decameric half-sites, and data suggest one p53 dimer in the tetramer binds to each half-site. Despite a broad literature describing p53 binding DNA, unanswered questions remain, due partly to the need for more quantitative and structural studies with full length protein. Here we describe a single molecule fluorescence system to visualize full length p53 tetramers binding DNA in real time. The data revealed a dynamic interaction in which tetrameric p53/DNA complexes assembled and disassembled without a dimer/DNA intermediate. On a wild type DNA containing two half sites, p53/DNA complexes existed in two kinetically distinct populations. p53 tetramers bound response elements containing only one half site to form a single population of complexes with reduced kinetic stability. Altering the spacing and helical phasing between two half sites affected both the population distribution of p53/DNA complexes and their kinetic stability. Our real time single molecule measurements of full length p53 tetramers binding DNA reveal the parameters that define the stability of p53/DNA complexes, and provide insight into the pathways by which those complexes assemble.
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http://dx.doi.org/10.1038/s41598-020-73234-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528078PMC
September 2020

Neonatal Lead (Pb) Exposure and DNA Methylation Profiles in Dried Bloodspots.

Int J Environ Res Public Health 2020 09 17;17(18). Epub 2020 Sep 17.

Department of Environmental Health Sciences, University of Michigan, Ann Arbor, MI 48109, USA.

Lead (Pb) exposure remains a major concern in the United States (US) and around the world, even following the removal of Pb from gasoline and other products. Environmental Pb exposures from aging infrastructure and housing stock are of particular concern to pregnant women, children, and other vulnerable populations. Exposures during sensitive periods of development are known to influence epigenetic modifications which are thought to be one mechanism of the Developmental Origins of Health and Disease (DOHaD) paradigm. To gain insights into early life Pb exposure-induced health risks, we leveraged neonatal dried bloodspots in a cohort of children from Michigan, US to examine associations between blood Pb levels and concomitant DNA methylation profiles ( = 96). DNA methylation analysis was conducted via the Infinium MethylationEPIC array and Pb levels were assessed via high resolution inductively coupled plasma mass spectrometry (HR-ICP-MS). While at-birth Pb exposure levels were relatively low (average 0.78 µg/dL, maximum of 5.27 ug/dL), we identified associations between DNA methylation and Pb at 33 CpG sites, with the majority (82%) exhibiting reduced methylation with increasing Pb exposure (q < 0.2). Biological pathways related to development and neurological function were enriched amongst top differentially methylated genes by -value. In addition to increases/decreases in methylation, we also demonstrate that Pb exposure is related to increased variability in DNA methylation at 16 CpG sites. More work is needed to assess the accuracy and precision of metals assessment using bloodspots, but this study highlights the utility of this unique resource to enhance environmental epigenetics research around the world.
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http://dx.doi.org/10.3390/ijerph17186775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559513PMC
September 2020

Mercury exposure in relation to sleep duration, timing, and fragmentation among adolescents in Mexico City.

Environ Res 2020 12 18;191:110216. Epub 2020 Sep 18.

Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Introduction: Mercury intoxication is known to be associated with adverse symptoms of fatigue and sleep disturbances, but whether low-level mercury exposure could affect sleep remains unclear. In particular, children may be especially vulnerable to both mercury exposures and to poor sleep. We sought to examine associations between mercury levels and sleep disturbances in Mexican youth.

Methods: The study sample comprised 372 youth from the Early Life Exposures to Environmental Toxicants (ELEMENT) cohort, a birth cohort from Mexico City. Sleep (via 7-day actigraphy) and concurrent urine mercury were assessed during a 2015 follow-up visit. Mercury was also assessed in mid-childhood hair, blood, and urine during an earlier study visit, and was considered a secondary analysis. We used linear regression and varying coefficient models to examine non-linear associations between Hg exposure biomarkers and sleep duration, timing, and fragmentation. Unstratified and sex-stratified analyses were adjusted for age and maternal education.

Results: During the 2015 visit, participants were 13.3 ± 1.9 years, and 48% were male. There was not a cross-sectional association between urine Hg and sleep characteristics. In secondary analysis using earlier biomarkers of Hg, lower and higher blood Hg exposure was associated with longer sleep duration among girls only. In both boys and girls, Hg biomarker levels in 2008 were associated with later adolescent sleep midpoint (for Hg urine in girls, and for blood Hg in boys). For girls, each unit log Hg was associated with 0.2 h later midpoint (95% CI 0 to 0.4), and for boys each unit log Hg was associated with a 0.4 h later sleep midpoint (95% CI 0.1 to 0.8).

Conclusions: There were mostly null associations between Hg exposure and sleep characteristics among Mexican children. Yet, in both boys and girls, higher Hg exposure in mid-childhood (measured in urine and blood, respectively) was related to later sleep timing in adolescence.
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http://dx.doi.org/10.1016/j.envres.2020.110216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750915PMC
December 2020

Low levels of salivary metals, oral microbiome composition and dental decay.

Sci Rep 2020 09 4;10(1):14640. Epub 2020 Sep 4.

Center for Molecular and Clinical Epidemiology of Infectious Diseases, University of Michigan School of Public Health, 1415 Washington Heights, Ann Arbor, MI, 48109-2029, USA.

Salivary microbiome composition can change following exposure to environmental toxicants, e.g., heavy metals. We hypothesized that levels of salivary nutrients and metals would correlate with salivary microbiome composition and be associated with dental decay. Here we assess the salivary concentrations of 5 essential minerals (cobalt, copper, manganese, molybdenum, and zinc), 4 metals with some evidence of normal physiological function (chromium, nickel, tungsten, and vanadium), and 12 with known toxicity (antimony, arsenic, barium, beryllium, cadmium, cesium, lead, mercury, platinum, thallium, tin, and uranium), and their associations with salivary microbiome composition and dental decay in 61 children and adults. 16 metals were detected in 54% of participants; 8 were found in all. Marked differences in salivary bacterial taxa were associated with levels of antimony, arsenic, and mercury, after adjusting for multiple testing. Further, antimony levels were associated with the presence of decayed teeth. Thus, salivary metal levels, even at low concentrations, may impact oral health.
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http://dx.doi.org/10.1038/s41598-020-71495-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474081PMC
September 2020

The importance of lean mass and iron deficiency when comparing hemoglobin mass in male and female athletic groups.

J Appl Physiol (1985) 2020 10 3;129(4):855-863. Epub 2020 Sep 3.

Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado.

Hemoglobin mass (Hbmass) is important for athletes because it helps determine maximal aerobic power. This study examined how lean mass, iron deficiency (ID), and sex influence Hbmass in athletic and nonathletic groups. NCAA Division I student athletes (21 men, 75 women; altitude: 1,625 m) were recruited from six athletic teams; 14 male and 12 female full-time students (non-varsity athletes) served as control subjects. Hbmass, body composition, and iron homeostasis parameters, including ferritin, soluble transferrin receptor (sTfR), hepcidin, erythroferrone, and 10 inflammatory cytokines, were measured two to four times across a competitive/training season. ID was defined as ferritin < 25 ng/mL. Hbmass was more closely related to lean mass ( = 0.90) than body mass ( = 0.69, < 0.01). Compared with female subjects, male subjects had 19.9% higher Hbmass relative to body mass (Hbmass) but only 7.5% higher Hbmass relative to lean mass (Hbmass) (both < 0.001). Prevalence of ID was higher in female than male subjects (47% vs. 9%, < 0.01) but did not vary between groups. Hbmass was 5% lower in ID vs. non-ID female subjects; Hbmass was not different. ID was associated with lower hepcidin, elevated sTfR, and elevated erythroferrone but not with differences in inflammatory cytokines. Hbmass varied significantly between athletic groups and across sex, but the majority of these differences are explained by differences in lean mass. ID was common in female subjects and was associated with lower Hbmass and hepcidin but not with differences in Hbmass or inflammatory cytokines. Hbmass relative to lean mass seems advantageous when monitoring iron deficiency. Differences in hemoglobin mass (Hbmass) between groups and across sex are primarily due to differences in lean mass. Iron deficiency (ID) independently decreases Hbmass; this effect is best characterized with Hbmass relative to lean mass. ID is common in females and is associated with lower hepcidin and elevated erythroferrone but not with differences in inflammatory cytokines. Hbmass relative to lean mass accurately quantifies hematological alterations secondary to iron deficiency.
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http://dx.doi.org/10.1152/japplphysiol.00391.2020DOI Listing
October 2020

Maternal lipid levels across pregnancy impact the umbilical cord blood lipidome and infant birth weight.

Sci Rep 2020 08 26;10(1):14209. Epub 2020 Aug 26.

Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Major alterations in metabolism occur during pregnancy enabling the mother to provide adequate nutrients to support infant development, affecting birth weight (BW) and potentially long-term risk of obesity and cardiometabolic disease. We classified dynamic changes in the maternal lipidome during pregnancy and identified lipids associated with Fenton BW z-score and the umbilical cord blood (CB) lipidome. Lipidomics was performed on first trimester maternal plasma (M1), delivery maternal plasma (M3), and CB plasma in 106 mother-infant dyads. Shifts in the maternal and CB lipidome were consistent with the selective transport of long-chain polyunsaturated fatty acids (PUFA) as well as lysophosphatidylcholine (LysoPC) and lysophosphatidylethanolamine (LysoPE) species into CB. Partial correlation networks demonstrated fluctuations in correlations between lipid groups at M1, M3, and CB, signifying differences in lipid metabolism. Using linear models, LysoPC and LysoPE groups in CB were positively associated with BW. M1 PUFA containing triglycerides (TG) and phospholipids were correlated with CB LysoPC and LysoPE species and total CB polyunsaturated TGs. These results indicate that early gestational maternal lipid levels influence the CB lipidome and its relationship with BW, suggesting an opportunity to modulate maternal diet and improve long-term offspring cardiometabolic health.
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http://dx.doi.org/10.1038/s41598-020-71081-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449968PMC
August 2020

Mitochondrial Epigenetics and Environmental Health: Making a Case for Endocrine Disrupting Chemicals.

Toxicol Sci 2020 11;178(1):16-25

Department of Food Science and Human Nutrition.

Recent studies implicate mitochondrial dysfunction in the development and progression of numerous chronic diseases, which may be partially due to modifications in mitochondrial DNA (mtDNA). There is also mounting evidence that epigenetic modifications to mtDNA may be an additional layer of regulation that controls mitochondrial biogenesis and function. Several environmental factors (eg, smoking, air pollution) have been associated with altered mtDNA methylation in a handful of mechanistic studies and in observational human studies. However, little is understood about other environmental contaminants that induce mtDNA epigenetic changes. Numerous environmental toxicants are classified as endocrine disrupting chemicals (EDCs). Beyond their actions on hormonal pathways, EDC exposure is associated with elevated oxidative stress, which may occur through or result in mitochondrial dysfunction. Although only a few studies have assessed the impacts of EDCs on mtDNA methylation, the current review provides reasons to consider mtDNA epigenetic disruption as a mechanism of action of EDCs and reviews potential limitations related to currently available evidence. First, there is sufficient evidence that EDCs (including bisphenols and phthalates) directly target mitochondrial function, and more direct evidence is needed to connect this to mtDNA methylation. Second, these and other EDCs are potent modulators of nuclear DNA epigenetics, including DNA methylation and histone modifications. Finally, EDCs have been shown to disrupt several modulators of mtDNA methylation, including DNA methyltransferases and the mitochondrial transcription factor A/nuclear respiratory factor 1 pathway. Taken together, these studies highlight the need for future research evaluating mtDNA epigenetic disruption by EDCs and to detail specific mechanisms responsible for such disruptions.
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http://dx.doi.org/10.1093/toxsci/kfaa129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818895PMC
November 2020

Trimester-Specific Associations of Prenatal Lead Exposure With Infant Cord Blood DNA Methylation at Birth.

Epigenet Insights 2020 20;13:2516865720938669. Epub 2020 Jul 20.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.

Gestational exposure to lead (Pb) adversely impacts offspring health through multiple mechanisms, one of which is the alteration of the epigenome including DNA methylation. This study aims to identify differentially methylated CpG sites associated with trimester-specific maternal Pb exposure in umbilical cord blood (UCB) leukocytes. Eighty-nine mother-child dyads from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) longitudinal birth cohorts with available UCB samples were selected for DNA methylation analysis via the Infinium Methylation EPIC BeadChip, which quantifies methylation at >850 000 CpG sites. Maternal blood lead levels (BLLs) during each trimester (T1: 6.56 ± 5.35 µg/dL; T2: 5.93 ± 5.00 µg/dL; T3: 6.09 ± 4.51 µg/dL), bone Pb (patella: 11.8 ± 9.25 µg/g; tibia: 11.8 ± 6.73 µg/g), a measure of cumulative Pb exposure, and UCB Pb (4.86 ± 3.74 µg/dL) were measured. After quality control screening, data from 786 024 CpG sites were used to identify differentially methylated positions (DMPs) and differentially methylated regions (DMRs) by Pb biomarkers using separate linear regression models, controlling for sex and estimated UCB cell-type proportions. We identified 3 DMPs associated with maternal T1 BLL, 2 with T3 BLL, and 2 with tibia bone Pb. We identified one DMR within associated with T1 BLL, one located at chr6:30095136-30095295 with T3 BLL, and one within with tibia bone Pb (adjusted -value < .05). Pathway analysis identified 15 overrepresented gene pathways for differential methylation that overlapped among all 3 trimesters with the largest overlap between T1 and T2 (adjusted -value < .05). Pathways of interest include nodal signaling pathway and neurological system processes. These data provide evidence for differential methylation by prenatal Pb exposure that may be trimester-specific.
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http://dx.doi.org/10.1177/2516865720938669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372614PMC
July 2020

'As soon as you've been there, it makes it personal': The experience of health-care staff shadowing patients at the end of life.

Health Expect 2020 10 19;23(5):1259-1268. Epub 2020 Jul 19.

The Point of Care Foundation, London, UK.

Background: Patient shadowing is an experiential technique intended to enable those who shadow to understand care experience from the patient's point of view. It is used in quality improvement to bring about change that focuses on what is important for patients.

Aim: To explore the acceptability of patient shadowing for health-care staff, the impact of the experience and subsequent motivations to make improvements.

Method: A qualitative study with a diverse sample of 20 clinical and non-clinical health-care staff in different end-of-life settings. Data were analysed thematically.

Results: Anticipated anxieties about shadowing did not materialize in participant accounts, although for some it was a deeply emotional experience, intensified by being with patients who were at the end of life. Shadowing not only impacted on participants personally, but also promoted better insights into the experience of patients, thus focusing their improvement efforts. Participants reported that patients and families who were shadowed welcomed additional caring attention.

Conclusion: With the right preparation and support, patient shadowing is a technique that engages and motivates health-care staff to improve patient-centred care.
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http://dx.doi.org/10.1111/hex.13107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696112PMC
October 2020

The epigenetic regulator ICU11 as an accessory protein of Polycomb Repressive Complex 2.

Proc Natl Acad Sci U S A 2020 07 29;117(28):16660-16666. Epub 2020 Jun 29.

Department of Cell and Developmental Biology, John Innes Centre, Colney Lane, NR47UH Norwich, United Kingdom;

Molecular mechanisms enabling the switching and maintenance of epigenetic states are not fully understood. Distinct histone modifications are often associated with ON/OFF epigenetic states, but how these states are stably maintained through DNA replication, yet in certain situations switch from one to another remains unclear. Here, we address this problem through identification of INCURVATA11 (ICU11) as a Polycomb Repressive Complex 2 accessory protein. ICU11 robustly immunoprecipitated in vivo with PRC2 core components and the accessory proteins, EMBRYONIC FLOWER 1 (EMF1), LIKE HETEROCHROMATIN PROTEIN1 (LHP1), and TELOMERE_REPEAT_BINDING FACTORS (TRBs). encodes a 2-oxoglutarate-dependent dioxygenase, an activity associated with histone demethylation in other organisms, and mutant plants show defects in multiple aspects of the epigenome. To investigate its primary molecular function we identified the () as a direct target and found disrupted the cold-induced, Polycomb-mediated silencing underlying vernalization. prevented reduction in H3K36me3 levels normally seen during the early cold phase, supporting a role for ICU11 in H3K36me3 demethylation. This was coincident with an attenuation of H3K27me3 at the internal nucleation site in , and reduction in H3K27me3 levels across the body of the gene after plants were returned to the warm. Thus, ICU11 is required for the cold-induced epigenetic switching between the mutually exclusive chromatin states at , from the active H3K36me3 state to the silenced H3K27me3 state. These data support the importance of physical coupling of histone modification activities to promote epigenetic switching between opposing chromatin states.
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http://dx.doi.org/10.1073/pnas.1920621117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368280PMC
July 2020

Optimizing Reconstruction in Craniosynostosis: Review of Nonsyndromic Patients Treated With a Novel Technique.

J Craniofac Surg 2020 Jul-Aug;31(5):1312-1317

Division of Plastic and Reconstructive Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY.

Purpose: Open cranial vault remodeling (CVR) with autologous split calvarial bone grafts redistributes and recontours an abnormal calvarium to create an expanded cranial vault in patients with craniosynostosis. We report a 12-year retrospective review of 162 nonsyndromic patients who underwent operative repair using our previously-described technique which portends excellent surgical outcomes and can be applied to patients of any age group and with any variety of suture fusion.

Methods: Data was gathered on patients who underwent CVR from 2005 to 2016. Surgical records for each patient were analyzed and included operative time, estimated blood loss, and intraoperative transfusion volumes. Intraoperative and postoperative complications, the need for revision surgery, postoperative length of stay, and follow-up records were also reviewed. Syndromic patients were excluded, as well as patients with incomplete data sets. Patients who underwent either anterior or posterior vault remodeling were compared.

Results: A total of 162 patients were included in this case series. Patients undergoing anterior CVR were significantly older than those undergoing posterior CVR (13.3 versus 11.0 months, P < 0.015) and also had significantly greater intraoperative red blood transfusion volumes (20.3 versus 15.3cc/kg, P < 0.0207) and longer operative time than posterior CVR patients (274.9 versus 216.7 minutes, P < 0.0001). No patients required reoperation for resorption or recurrence or persistent contour irregularities. There were no visual or neurological complications. Calvarial bone was successfully split in 100% of cases.

Conclusions: This surgical approach to CVR results in good surgical outcomes with a low recurrence rate, while also maximizing operative efficiency, and minimizing total blood loss and transfusion volume. This technique can be applied to any affected suture in a patient with craniosynostosis and in patients of any age group.
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http://dx.doi.org/10.1097/SCS.0000000000006693DOI Listing
November 2020

The domesticated transposase ALP2 mediates formation of a novel Polycomb protein complex by direct interaction with MSI1, a core subunit of Polycomb Repressive Complex 2 (PRC2).

PLoS Genet 2020 05 28;16(5):e1008681. Epub 2020 May 28.

Institute of Molecular Plant Science, School of Biological Sciences, University of Edinburgh, Daniel Rutherford Building, Max Born Crescent, Edinburgh, United Kingdom.

A large fraction of plant genomes is composed of transposable elements (TE), which provide a potential source of novel genes through "domestication"-the process whereby the proteins encoded by TE diverge in sequence, lose their ability to catalyse transposition and instead acquire novel functions for their hosts. In Arabidopsis, ANTAGONIST OF LIKE HETEROCHROMATIN PROTEIN 1 (ALP1) arose by domestication of the nuclease component of Harbinger class TE and acquired a new function as a component of POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), a histone H3K27me3 methyltransferase involved in regulation of host genes and in some cases TE. It was not clear how ALP1 associated with PRC2, nor what the functional consequence was. Here, we identify ALP2 genetically as a suppressor of Polycomb-group (PcG) mutant phenotypes and show that it arose from the second, DNA binding component of Harbinger transposases. Molecular analysis of PcG compromised backgrounds reveals that ALP genes oppose silencing and H3K27me3 deposition at key PcG target genes. Proteomic analysis reveals that ALP1 and ALP2 are components of a variant PRC2 complex that contains the four core components but lacks plant-specific accessory components such as the H3K27me3 reader LIKE HETEROCHROMATION PROTEIN 1 (LHP1). We show that the N-terminus of ALP2 interacts directly with ALP1, whereas the C-terminus of ALP2 interacts with MULTICOPY SUPPRESSOR OF IRA1 (MSI1), a core component of PRC2. Proteomic analysis reveals that in alp2 mutant backgrounds ALP1 protein no longer associates with PRC2, consistent with a role for ALP2 in recruitment of ALP1. We suggest that the propensity of Harbinger TE to insert in gene-rich regions of the genome, together with the modular two component nature of their transposases, has predisposed them for domestication and incorporation into chromatin modifying complexes.
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http://dx.doi.org/10.1371/journal.pgen.1008681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282668PMC
May 2020

The effect of LRRK2 loss-of-function variants in humans.

Nat Med 2020 06 27;26(6):869-877. Epub 2020 May 27.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD), 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
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http://dx.doi.org/10.1038/s41591-020-0893-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303015PMC
June 2020

Preoperative Evaluation of Craniopagus Twins: Anatomy, Imaging Techniques, and Surgical Management.

AJNR Am J Neuroradiol 2020 06 21;41(6):951-959. Epub 2020 May 21.

Departments of Radiology (A.E.G.-Y., J.M.F.).

Craniopagus twins are a rare congenital malformation in which twins are conjoined at the head. Although there is high prenatal and postnatal mortality for craniopagus twins, successful separation has become more common due to advances in neuroimaging, neuroanesthesia, and neurosurgical techniques. Joined brain tissue, shared arteries and veins, and defects in the skull and dura make surgery technically challenging, and neuroimaging plays an important role in preoperative planning. Drawing on our experience from consultation for multiple successful separations of craniopagus twins, we discuss what radiologists need to know about the anatomy, classification, imaging techniques, and surgical management of craniopagus twins.
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http://dx.doi.org/10.3174/ajnr.A6571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342745PMC
June 2020

Release of Human TFIIB from Actively Transcribing Complexes Is Triggered upon Synthesis of 7- and 9-nt RNAs.

J Mol Biol 2020 06 14;432(14):4049-4060. Epub 2020 May 14.

Department of Biochemistry, University of Colorado Boulder, 596 UCB, Boulder, CO 80309, USA. Electronic address:

RNA polymerase II (Pol II) and its general transcription factors assemble on the promoters of mRNA genes to form large macromolecular complexes that initiate transcription in a regulated manner. During early transcription, these complexes undergo dynamic rearrangement and disassembly as Pol II moves away from the start site of transcription and transitions into elongation. One step in disassembly is the release of the general transcription factor TFIIB, although the mechanism of release and its relationship to the activity of transcribing Pol II is not understood. We developed a single-molecule fluorescence transcription system to investigate TFIIB release in vitro. Leveraging our ability to distinguish active from inactive complexes, we found that nearly all transcriptionally active complexes release TFIIB during early transcription. Release is not dependent on the contacts TFIIB makes with its recognition element in promoter DNA. We identified two different points in early transcription at which release is triggered, reflecting heterogeneity across the population of actively transcribing complexes. TFIIB releases after both trigger points with similar kinetics, suggesting the rate of release is independent of the molecular transformations that prompt release. Together our data support the model that TFIIB release is important for Pol II to successfully escape the promoter as initiating complexes transition into elongation complexes.
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http://dx.doi.org/10.1016/j.jmb.2020.05.005DOI Listing
June 2020