Biology subjects

Nguyen, T. L.

Publications and source records attributed to Nguyen, T. L..

3 recordsLinked to original sources

bioRxiv2018

Associations between environmental breast cancer risk factors and DNA methylation-based risk-predicting measures

BackgroundGenome-wide average DNA methylation (GWAM) and epigenetic age acceleration have been suggested to predict breast cancer risk. We aimed to investigate the relationships between these putative risk-predicting measures and environmental breast cancer risk factors.\n\nMethodsUsing the Illumina HumanMethylation450K assay methylation data, we calculated GWAM and epigenetic age acceleration for 132 female twin pairs and their 215 sisters. Linear regression was used to estimate associations between these risk-predicting measures and multiple breast cancer risk factors. Within-pair analysis was performed for the 132 twin pairs.\n\nResultsGWAM was negatively associated with number of live births, and positively with age at first live birth (both P<0.05). Epigenetic age acceleration was positively associated with body mass index (BMI), smoking, alcohol drinking and age at menarche, and negatively with age at first live birth (all P<0.05), and the associations with BMI, alcohol drinking and age at first live birth remained in the within-pair analysis.\n\nConclusionsThis exploratory study shows that lifestyle and hormone-related breast cancer risk factors are associated with DNA methylation-based measures that could predict breast cancer risk. The associations of epigenetic age acceleration with BMI, alcohol drinking and age at first live birth are unlikely to be due to familial confounding.

epidemiology↗

bioRxiv2017

Inference about causation between body mass index and DNA methylation in blood from a twin family study

BackgroundSeveral studies have reported DNA methylation in blood to be associated with body mass index (BMI), but only a few have investigated causal aspects of the association. We used a twin family design to assess this association at two life points and applied a novel analytical approach to investigate the evidence for causality.\n\nMethodsThe methylation profile of DNA from peripheral blood was measured for 479 Australian women (mean age 56 years) from 130 twin families. Linear regression was used to estimate the associations of methylation at ~410 000 cytosine-guanine dinucleotides (CpG), and of the average methylation at ~20 000 genes, with current BMI, BMI at age 18-21 years, and the change between the two (BMI change). A novel regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess causation.\n\nResultsAt 5% false discovery rate, nine, six and 12 CpGs at 24 loci were associated with current BMI, BMI at age 18-21 years and BMI change, respectively. The average methylation of BHLHE40 and SOCS3 loci was associated with current BMI, and of PHGDH locus was associated with BMI change. From the ICE FALCON analyses with BMI as the predictor and methylation as the outcome, a womans methylation level was associated with her co-twins BMI, and the association disappeared conditioning on her own BMI, consistent with BMI causing methylation. To the contrary, using methylation as the predictor and BMI as the outcome, a womans BMI was not associated with her co-twins methylation level, consistent with methylation not causing BMI.\n\nConclusionFor middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with current BMI, BMI at age 18-21 years and BMI change. Our study suggests that BMI has a causal effect on peripheral blood DNA methylation.

epidemiology↗

bioRxiv2017

In vivo cross-linking and transmembrane helix dynamics support a non-piston model of signaling within E. coli EnvZ

In Gram-negative bacteria, porins span the outer membrane and control the influx of several prominent groups of antibiotics. Thus, it should not be surprising that expression of these porins is often altered in clinical isolates exhibiting multidrug resistance (MDR). The major regulator of porin expression in Escherichia coli is EnvZ, a canonical sensor histidine kinase (SHK). It allosterically processes periplasmic interactions with MzrA and cytoplasmic osmosensing into a single unified change in the ratio of its kinase and phosphatase activities. Unfortunately, the role of the EnvZ transmembrane domain (TMD) in bidirectional communication of these signals remains not well understood. Here, we employed in vivo sulfhydryl-reactivity to probe the dynamics of the TM2 helices and demonstrate that upon stimulus perception, only the region proximal to the periplasm undergoes conformational rearrangement. Furthermore, in silico coarse-grained molecular dynamics (CG-MD) simulations with aromatically tuned variants of EnvZ TM2 demonstrate the existence of both tilting and azimuthal rotational components to transmembrane communication while ruling out piston-type repositioning of TM2. Finally, in contrast to a similar analysis of TM1, we identified position-specific mutants possessing a \"flipped\" phenotype by dual-color fluorescent reporter analysis suggesting that both the periplasmic and cytoplasmic ends of TM2 are critical for maintenance of EnvZ signal output. Taken together, these data strongly support that EnvZ employs a non-piston-type mechanism during transmembrane communication. We conclude by discussing these results within the context of allosteric processing by EnvZ and propose that these results can be used to predict and classify transmembrane communication by various SHKs.\n\nImportanceThe EnvZ sensor histidine kinase serves as the major regulator of porin expression within Escherichia coli. A long-standing question is how stimulus perception by a bacterial receptor on one side of a biological membrane is transmitted to the opposite side of the membrane. To address this question, we monitored the dynamics of the transmembrane domain of EnvZ in vivo and coupled these results with in silico simulations of membrane-embedded EnvZ transmembrane domains. Taken together, these results demonstrate that detection of osmotic stress by the cytoplasmic domain of EnvZ results in non-piston communication across the inner membrane of E. coli. Thus, in addition to understanding how EnvZ regulates porin balance and antibiotic influx, these results contribute to answering the long-standing question of how transmembrane communication is performed by bacterial receptors. Our work concludes with a framework that correlates receptor domain composition and signal transduction mechanisms that could be employed by other research groups on their particular receptors of interest.

biochemistry↗