DNA methylation signatures in airway cells from adult children of asthmatic mothers reflect subtypes of severe asthma.

Maternal asthma (MA) is among the most consistent risk factors for asthma in children. Possible mechanisms for this observation are epigenetic modifications in utero that have lasting effects on developmental programs in children of mothers with asthma. To test this hypothesis, we performed differential DNA methylation analyses of 398,186 individual CpG sites in primary bronchial epithelial cells (BECs) from 42 nonasthma controls and 88 asthma cases, including 56 without MA (NMA) and 32 with MA. We used weighted gene coexpression network analysis (WGCNA) of 69 and 554 differentially methylated CpGs (DMCs) that were specific to NMA and MA cases, respectively, compared with controls. WGCNA grouped 66 NMA-DMCs and 203 MA-DMCs into two and five comethylation modules, respectively. The eigenvector of one MA-associated module (turquoise) was uniquely correlated with 85 genes expressed in BECs and enriched for 36 pathways, 16 of which discriminated between NMA and MA using machine learning. Genes in all 16 pathways were decreased in MA compared with NMA cases (P = 7.1 × 10−3), a finding that replicated in nasal epithelial cells from an independent cohort (P = 0.02). Functional interpretation of these pathways suggested impaired T cell signaling and responses to viral and bacterial pathogens. The MA-associated turquoise module eigenvector was additionally correlated with clinical features of severe asthma and reflective of type 2 (T2)-low asthma (i.e., low total serum immunoglobulin E, fractional exhaled nitric oxide, and eosinophilia). Overall, these data suggest that MA alters diverse epigenetically mediated pathways that lead to distinct subtypes of severe asthma in adults, including hard-to-treat T2-low asthma.

Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers.

BACKGROUND: The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. OBJECTIVE: We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. METHODS: We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell-derived IL-1ß levels were measured by means of ELISA. RESULTS: Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1ß, an innate inflammatory mediator. CONCLUSIONS: The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.

Genome-Wide Methylation Study Identifies an IL-13-induced Epigenetic Signature in Asthmatic Airways.

RATIONALE: Epigenetic changes to airway cells have been proposed as important modulators of the effects of environmental exposures on airway diseases, yet no study to date has shown epigenetic responses to exposures in the airway that correlate with disease state. The type 2 cytokine IL-13 is a key mediator of allergic airway diseases, such as asthma, and is up-regulated in response to many asthma-promoting exposures. OBJECTIVES: To directly study the epigenetic response of airway epithelial cells (AECs) to IL-13 and test whether IL-13-induced epigenetic changes differ between individuals with and without asthma. METHODS: Genome-wide DNA methylation and gene expression patterns were studied in 58 IL-13-treated and untreated primary AEC cultures and validated in freshly isolated cells of subjects with and without asthma using the Illumina Human Methylation 450K and HumanHT-12 BeadChips. IL-13-mediated comethylation modules were identified and correlated with clinical phenotypes using weighted gene coexpression network analysis. MEASUREMENTS AND MAIN RESULTS: IL-13 altered global DNA methylation patterns in cultured AECs and were significantly enriched near genes associated with asthma. Importantly, a significant proportion of this IL-13 epigenetic signature was validated in freshly isolated AECs from subjects with asthma and clustered into two distinct modules, with module 1 correlated with asthma severity and lung function and module 2 with eosinophilia. CONCLUSIONS: These results suggest that a single exposure of IL-13 may selectively induce long-lasting DNA methylation changes in asthmatic airways that alter specific AEC pathways and contribute to asthma phenotypes.

Maternal asthma and microRNA regulation of soluble HLA-G in the airway.

BACKGROUND: We previously reported an interaction between maternal asthma and the child's HLA-G genotype on the child's subsequent risk for asthma. The implicated single nucleotide polymorphism at +3142 disrupted a target site for the microRNA (miR)-152 family. We hypothesized that the interaction effect might be mediated by these miRs. OBJECTIVE: The objective of this study was to test this hypothesis in adults with asthma who are a subset of the same subjects who participated in our earlier family-based studies. METHODS: We measured soluble HLA-G (sHLA-G) concentrations in bronchoalveolar lavage fluid (n = 36) and plasma (n = 57) from adult asthmatic subjects with and without a mother with asthma, and HLA-G and miR-152 family (miR-148a, miR-148b, and miR-152) transcript levels in airway epithelial cells from the same subjects. RESULTS: miR-148b levels were significantly increased in airway epithelial cells from asthmatic subjects with an asthmatic mother compared with those seen in asthmatic subjects without an asthmatic mother, and +3142 genotypes were associated with sHLA-G concentrations in bronchoalveolar lavage fluid among asthmatic subjects with an asthmatic mother but not among those with a nonasthmatic mother. Neither effect was observed in the plasma (sHLA-G) or white blood cells (miRNA). CONCLUSION: These combined results are consistent with +3142 allele-specific targeting of HLA-G by the miR-152 family and support our hypothesis that miRNA regulation of sHLA-G in the airway is influenced by both the asthma status of the subject's mother and the subject's genotype. Moreover, we demonstrate that the effects of maternal asthma on the gene regulatory landscape in the airways of the mother's children persist into adulthood.

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Background: Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. Methods: The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Results: Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Conclusion: Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Evaluation in a porcine wound model and long-term clinical assessment of an autologous heterogeneous skin construct used to close full-thickness wounds.

Acute and chronic wounds involving deeper layers of the skin are often not adequately healed by dressings alone and require therapies such as skin grafting, skin substitutes, or growth factors. Here we report the development of an autologous heterogeneous skin construct (AHSC) that aids wound closure. AHSC is manufactured from a piece of healthy full-thickness skin. The manufacturing process creates multicellular segments, which contain endogenous skin cell populations present within hair follicles. These segments are physically optimized for engraftment within the wound bed. The ability of AHSC to facilitate closure of full thickness wounds of the skin was evaluated in a swine model and clinically in 4 patients with wounds of different etiologies. Transcriptional analysis demonstrated high concordance of gene expression between AHSC and native tissues for extracellular matrix and stem cell gene expression panels. Swine wounds demonstrated complete wound epithelialization and mature stable skin by 4 months, with hair follicle development in AHSC-treated wounds evident by 15 weeks. Biomechanical, histomorphological, and compositional analysis of the resultant swine and human skin wound biopsies demonstrated the presence of epidermal and dermal architecture with follicular and glandular structures that are similar to native skin. These data suggest that treatment with AHSC can facilitate wound closure.

Avoiding future controversies in the Alzheimer's disease space through understanding the aducanumab data and FDA review.

Key points of disagreement between the aducanumab FDA statistical review, which had primarily negative conclusions, and the clinical review, which had primarily positive conclusions, were investigated. Results from secondary endpoints in positive Study 302 were significant and these endpoints provided meaningful additional information. Findings indicate the statistical review of the aducanumab data was incorrect in a number of key areas. Greater placebo decline was not responsible for the significant results in Study 302. Correlations did exist between reduction in ß-amyloid and clinical outcomes. Missing data and functional unblinding did not likely bias results. In contrast, the clinical review went too far in saying the negative results in Study 301 did not detract from the positive results in Study 302, as all clinical data should be considered in the evaluation, and the clinical review accepted the company's explanation for divergence of the results between the studies although much of the divergence remained unexplained. Interestingly, both the statistical review and the clinical review considered the available efficacy evidence despite both studies being terminated early. Implications of these findings include that the divergence in results seen in the two phase 3 aducanumab studies can be expected in other studies with similar design and analysis. Therefore, further research is needed to determine if analysis methods other than MMRM and/or optimized outcomes will provide more consistent results across studies.

Molecular evolution of A-kinase anchoring protein (AKAP)-7: implications in comparative PKA compartmentalization.

BACKGROUND: A-Kinase Anchoring Proteins (AKAPs) are molecular scaffolding proteins mediating the assembly of multi-protein complexes containing cAMP-dependent protein kinase A (PKA), directing the kinase in discrete subcellular locations. Splice variants from the AKAP7 gene (AKAP15/18) are vital components of neuronal and cardiac phosphatase complexes, ion channels, cardiac Ca2+ handling and renal water transport. RESULTS: Shown in evolutionary analyses, the formation of the AKAP7-RI/RII binding domain (required for AKAP/PKA-R interaction) corresponds to vertebrate-specific gene duplication events in the PKA-RI/RII subunits. Species analyses of AKAP7 splice variants shows the ancestral AKAP7 splice variant is AKAP7α, while the ancestral long form AKAP7 splice variant is AKAP7γ. Multi-species AKAP7 gene alignments, show the recent formation of AKAP7δ occurs with the loss of native AKAP7γ in rats and basal primates. AKAP7 gene alignments and two dimensional Western analyses indicate that AKAP7γ is produced from an internal translation-start site that is present in the AKAP7δ cDNA of mice and humans but absent in rats. Immunofluorescence analysis of AKAP7 protein localization in both rat and mouse heart suggests AKAP7γ replaces AKAP7δ at the cardiac sarcoplasmic reticulum in species other than rat. DNA sequencing identified Human AKAP7δ insertion-deletions (indels) that promote the production of AKAP7γ instead of AKAP7δ. CONCLUSIONS: This AKAP7 molecular evolution study shows that these vital scaffolding proteins developed in ancestral vertebrates and that independent mutations in the AKAP7 genes of rodents and early primates has resulted in the recent formation of AKAP7δ, a splice variant of likely lesser importance in humans than currently described.

Assembly of the antifreeze glycoprotein/trypsinogen-like protease genomic locus in the Antarctic toothfish Dissostichus mawsoni (Norman).

To investigate the genomic architecture underlying the quintessential adaptive phenotype, antifreeze glycoprotein (AFGP) that enables Antarctic notothenioid survival in the frigid Southern Ocean, we isolated the AFGP genomic locus from a bacterial artificial chromosome library for Dissostichus mawsoni. Through extensive shotgun sequencing of pertinent clones and sequence assembly verifications, we reconstructed the highly repetitive AFGP genomic locus. The locus comprises two haplotypes of different lengths (363.6 kbp and 467.4 kbp) containing tandem AFGP, two TLP (trypsinogen-like protease), and surprisingly three chimeric AFGP/TLP, one of which was previously hypothesized to be a TLP-to-AFGP evolutionary intermediate. The ~100 kbp haplotype length variation results from different AFGP copy number, suggesting substantial dynamism existed in the evolutionary history of the AFGP gene family. This study provided the data for fine resolution sequence analyses that would yield insight into the molecular mechanisms of notothenioid AFGP gene family evolution driven by Southern Ocean glaciation.

GenoRisk: A polygenic risk score for Alzheimer's disease.

INTRODUCTION: Recent clinical trials are considering inclusion of more than just apolipoprotein E (APOE) ε4 genotype as a way of reducing variability in analysis of outcomes. METHODS: Case-control data were used to compare the capacity of age, sex, and 58 Alzheimer's disease (AD)-associated single nucleotide polymorphisms (SNPs) to predict AD status using several statistical models. Model performance was assessed with Brier scores and tenfold cross-validation. Genotype and sex × age estimates from the best performing model were combined with age and intercept estimates from the general population to develop a personalized genetic risk score, termed age, and sex-adjusted GenoRisk. RESULTS: The elastic net model that included age, age x sex interaction, allelic APOE terms, and 29 additional SNPs performed the best. This model explained an additional 19% of the heritable risk compared to APOE genotype alone and achieved an area under the curve of 0.747. DISCUSSION: GenoRisk could improve the risk assessment of individuals identified for prevention studies.

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study.

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid ß peptides (Aß1-40, Aß1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.

An evolutionary analysis of cAMP-specific Phosphodiesterase 4 alternative splicing.

BACKGROUND: Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the intracellular second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP). The cAMP-specific PDE family 4 (PDE4) is widely expressed in vertebrates. Each of the four PDE4 gene isoforms (PDE4 A-D) undergo extensive alternative splicing via alternative transcription initiation sites, producing unique amino termini and yielding multiple splice variant forms from each gene isoform termed long, short, super-short and truncated super-short. Many species across the vertebrate lineage contain multiple splice variants of each gene type, which are characterized by length and amino termini. RESULTS: A phylogenetic approach was used to visualize splice variant form genesis and identify conserved splice variants (genome conservation with EST support) across the vertebrate taxa. Bayesian and maximum likelihood phylogenetic inference indicated PDE4 gene duplication occurred at the base of the vertebrate lineage and reveals additional gene duplications specific to the teleost lineage. Phylogenetic inference and PDE4 splice variant presence, or absence as determined by EST screens, were further supported by the genomic analysis of select vertebrate taxa. Two conserved PDE4 long form splice variants were found in each of the PDE4A, PDE4B, and PDE4C genes, and eight conserved long forms from the PDE4 D gene. Conserved short and super-short splice variants were found from each of the PDE4A, PDE4B, and PDE4 D genes, while truncated super-short variants were found from the PDE4C and PDE4 D genes. PDE4 long form splice variants were found in all taxa sampled (invertebrate through mammals); short, super-short, and truncated super-short are detected primarily in tetrapods and mammals, indicating an increasing complexity in both alternative splicing and cAMP metabolism through vertebrate evolution. CONCLUSIONS: There was a progressive independent incorporation of multiple PDE4 splice variant forms and amino termini, increasing PDE4 proteome complexity from primitive vertebrates to humans. While PDE4 gene isoform duplicates with limited alternative splicing were found in teleosts, an expansion of both PDE4 splice variant forms, and alternatively spliced amino termini predominantly occurs in mammals. Since amino termini have been linked to intracellular targeting of the PDE4 enzymes, the conservation of amino termini in PDE4 splice variants in evolution highlights the importance of compartmentalization of PDE4-mediated cAMP hydrolysis.

Gender and Age Stratified Analyses of Nutrient and Dietary Pattern Associations with Circulating Lipid Levels Identify Novel Gender and Age-Specific Correlations.

Dyslipidemia is a precursor to a myriad of cardiovascular diseases in the modern world. Age, gender, and diet are known modifiers of lipid levels, however they are not frequently investigated in subset analyses. Food and nutrient intakes from National Health and Nutrition Examination Study 2001⁻2013 were used to assess the correlation between lipid levels (high-density lipoprotein (HDL) cholesterol, triglycerides (TG), low-density lipoprotein (LDL) cholesterol, and total cholesterol (TC):HDL cholesterol ratio) and nutritional intake using linear regression. Associations were initially stratified by gender and significant gender correlations were further stratified by age. Analyses were performed at both the dietary pattern and nutrient level. Dietary pattern and fat intake correlations agreed with the literature in direction and did not demonstrate gender or age effects; however, we observed gender and age interactions among other dietary patterns and individual nutrients. These effects were independent of ethnicity, caloric intake, socioeconomic status, and physical activity. Elevated HDL cholesterol levels correlated with increasing vitamin and mineral intake in females of child bearing age but not males or older females (≥65 years). Moreover, increases in magnesium and retinol intake correlated with HDL cholesterol improvement only in females (all age groups) and males (35⁻64), respectively. Finally, a large amount of gender-specific variation was associated with TG levels. Females demonstrated positive associations with sugar and carbohydrate while males show inverse associations with polyunsaturated fatty acid (PUFA) intake. The female-specific association increased with the ratio of carbohydrate: saturated fatty acid (SFA) intake, suggesting that gender specific dietary habits may underlie the observed TG-nutrient correlations. Our study provides evidence that a subset of previously established nutrient-lipid associations may be gender or age-specific. Such discoveries provide potential new avenues for further research into personalized nutritional approaches to treat dyslipidemia.

Global DNA methylation changes spanning puberty are near predicted estrogen-responsive genes and enriched for genes involved in endocrine and immune processes.

Background: The changes that occur during puberty have been implicated in susceptibility to a wide range of diseases later in life, many of which are characterized by sex-specific differences in prevalence. Both genetic and environmental factors have been associated with the onset or delay of puberty, and recent evidence has suggested a role for epigenetic changes in the initiation of puberty as well. Objective: To identify global DNA methylation changes that arise across the window of puberty in girls and boys. Methods: Genome-wide DNA methylation levels were measured using the Infinium 450K array. We focused our studies on peripheral blood mononuclear cells (PBMCs) from 30 girls and 25 boys pre- and post-puberty (8 and 14 years, respectively), in whom puberty status was confirmed by Tanner staging. Results: Our study revealed 347 differentially methylated probes (DMPs) in females and 50 DMPs in males between the ages of 8 and 14 years (FDR 5%). The female DMPs were in or near 312 unique genes, which were over-represented for having high affinity estrogen response elements (permutation P < 2.0 × 10-6), suggesting that some of the effects of estrogen signaling in puberty are modified through epigenetic mechanisms. Ingenuity Pathway Analysis (IPA) of the 312 genes near female puberty DMPs revealed significant networks enriched for immune and inflammatory responses as well as reproductive hormone signaling. Finally, analysis of gene expression in the female PBMCs collected at 14 years revealed modules of correlated transcripts that were enriched for immune and reproductive system functions, and include genes that are responsive to estrogen and androgen receptor signaling. The male DMPs were in or near 48 unique genes, which were enriched for adrenaline and noradrenaline biosynthesis (Enrichr P = 0.021), with no significant networks identified. Additionally, no modules were identified using post-puberty gene expression levels in males. Conclusion: Epigenetic changes spanning the window of puberty in females may be responsive to or modify hormonal changes that occur during this time and potentially contribute to sex-specific differences in immune-mediated and endocrine diseases later in life.

Effects of a Meal Replacement on Body Composition and Metabolic Parameters among Subjects with Overweight or Obesity.

Meal replacement plans are effective tools for weight loss and improvement of various clinical characteristics but not sustainable due to the severe energy restriction. The aim of the study was to evaluate the impact of meal replacement, specifically 388 kcal in total energy, on body composition and metabolic parameters in individuals with overweight and obesity from a Chinese population. A parallel, randomized controlled trial was performed with 174 participants (ChiCTR-OOC-17012000). The intervention group (N=86) was provided with a dinner meal replacement, and the control group (N=88) continued their routine diet as before. Body composition and blood parameters were assessed at 0, 4, 8, and 12 weeks. A post hoc analysis (least significant difference (LSD) test), repeated measurements, and paired T-test were used to compare each variable within and between groups. Significant (p < 0.001) improvements in body composition components were observed among the intervention group, including body weight (-4.3 ± 3.3%), body mass index (-4.3 ± 3.3%), waist circumference (-4.3 ± 4.4%), fat-free mass (-1.8 ± 2.9%), and body fat mass (-5.3 ± 8.8%). Body composition improvements corresponded with significant metabolic improvements of blood glucose (-4.7 ± 9.8%). Further improvements in visceral fat area (-7.7 ± 10.1%), accompanying with improvements in systolic (-3.7 ± 6.9%) and diastolic (-5.3 ± 7.7%) blood pressure, were only found in male subjects. To conclude, meal replacement intake with 388 kcal in total energy at dinner time for 12 weeks contributed to improvement in body composition and clinically significant metabolic parameters in both male and female participants with overweight/obesity. Additionally, glucose and blood pressure reduction were gender-specific highlighting the importance of gender stratification for design of nutritional intervention studies for improvement of health.

Correction: Nicodemus-Johnson, J.; et al. Fruit and Juice Epigenetic Signatures Are Associated with Independent Immunoregulatory Pathways. Nutrients 2017, 9, 752.

We would like to submit the following correction to our recently published paper [1] due to the error in illustration of the abbreviation eFORGE. The details are as follows:[...].

Fruit and Juice Epigenetic Signatures Are Associated with Independent Immunoregulatory Pathways.

Epidemiological evidence strongly suggests that fruit consumption promotes many health benefits. Despite the general consensus that fruit and juice are nutritionally similar, epidemiological results for juice consumption are conflicting. Our objective was to use DNA methylation marks to characterize fruit and juice epigenetic signatures within PBMCs and identify shared and independent signatures associated with these groups. Genome-wide DNA methylation marks (Illumina Human Methylation 450k chip) for 2,148 individuals that participated in the Framingham Offspring exam 8 were analyzed for correlations between fruit or juice consumption using standard linear regression. CpG sites with low P-values (P < 0.01) were characterized using Gene Set Enrichment Analysis (GSEA), Ingenuity Pathway Analysis (IPA), and epigenetic Functional element Overlap analysis of the Results of Genome Wide Association Study Experiments (eFORGE). Fruit and juice-specific low P-value epigenetic signatures were largely independent. Genes near the fruit-specific epigenetic signature were enriched among pathways associated with antigen presentation and chromosome or telomere maintenance, while the juice-specific epigenetic signature was enriched for proinflammatory pathways. IPA and eFORGE analyses implicate fruit and juice-specific epigenetic signatures in the modulation of macrophage (fruit) and B or T cell (juice) activities. These data suggest a role for epigenetic regulation in fruit and juice-specific health benefits and demonstrate independent associations with distinct immune functions and cell types, suggesting that these groups may not confer the same health benefits. Identification of such differences between foods is the first step toward personalized nutrition and ultimately the improvement of human health and longevity.

DNA methylation in lung cells is associated with asthma endotypes and genetic risk.

The epigenome provides a substrate through which environmental exposures can exert their effects on gene expression and disease risk, but the relative importance of epigenetic variation on human disease onset and progression is poorly characterized. Asthma is a heterogeneous disease of the airways, for which both onset and clinical course result from interactions between host genotype and environmental exposures, yet little is known about the molecular mechanisms for these interactions. We assessed genome-wide DNA methylation using the Infinium Human Methylation 450K Bead Chip and characterized the transcriptome by RNA sequencing in primary airway epithelial cells from 74 asthmatic and 41 nonasthmatic adults. Asthma status was based on doctor's diagnosis and current medication use. Genotyping was performed using various Illumina platforms. Our study revealed a regulatory locus on chromosome 17q12-21 associated with asthma risk and epigenetic signatures of specific asthma endotypes and molecular networks. Overall, these data support a central role for DNA methylation in lung cells, which promotes distinct molecular pathways of asthma pathogenesis and modulates the effects of genetic variation on disease risk and clinical heterogeneity.

Genome-Wide Gene Expression Analysis Shows AKAP13-Mediated PKD1 Signaling Regulates the Transcriptional Response to Cardiac Hypertrophy.

In the heart, scaffolding proteins such as A-Kinase Anchoring Proteins (AKAPs) play a crucial role in normal cellular function by serving as a signaling hub for multiple protein kinases including protein kinase D1 (PKD1). Under cardiac hypertrophic conditions AKAP13 anchored PKD1 activates the transcription factor MEF2 leading to subsequent fetal gene activation and hypertrophic response. We used an expression microarray to identify the global transcriptional response in the hearts of wild-type mice expressing the native form of AKAP13 compared to a gene-trap mouse model expressing a truncated form of AKAP13 that is unable to bind PKD1 (AKAP13-ΔPKD1). Microarray analysis showed that AKAP13-ΔPKD1 mice broadly failed to exhibit the transcriptional profile normally associated with compensatory cardiac hypertrophy following trans-aortic constriction (TAC). The identified differentially expressed genes in WT and AKAP13-ΔPKD1 hearts are vital for the compensatory hypertrophic response to pressure-overload and include myofilament, apoptotic, and cell growth/differentiation genes in addition to genes not previously identified as affected by AKAP13-anchored PKD1. Our results show that AKAP13-PKD1 signaling is critical for transcriptional regulation of key contractile, cell death, and metabolic pathways during the development of compensatory hypertrophy in vivo.