Genomic properties of variably methylated retrotransposons in mouse

Background: Transposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. We previously identified a genome-wide repertoire of candidate intracisternal A particle (IAP) TEs in mice that exhibit interindividual variability in this methylation (VM-IAPs) with implications for genome function. Results: Here we validate these metastable epialleles and discover a novel class that exhibit tissue specificity (tsVM-IAPs) in addition to those with uniform methylation in all tissues (constitutive- or cVM-IAPs); both types have the potential to regulate genes in cis . Screening for variable methylation at other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We identify sequences enriched within cVM-IAPs, but determine that these are not sufficient to confer epigenetic variability. CTCF is enriched at VM-IAPs with binding inversely correlated with DNA methylation. We uncover dynamic physical interactions between cVM-IAPs with low methylation ranges and other genomic loci, suggesting that VM-IAPs have the potential for long-range regulation. Conclusion: Our findings indicate that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs can result in inter-individual variability in transcriptional outcomes with implications for phenotypic variation

Predictability of biotic stress structures plant defence evolution

To achieve ecological and reproductive success, plants need to mitigate a multitude of stressors. The stressors encountered by plants are highly dynamic but typically vary predictably due to seasonality or correlations among stressors. As plants face physiological and ecological constraints in responses to stress, it can be beneficial for plants to evolve the ability to incorporate predictable patterns of stress in their life histories. Here, we discuss how plants predict adverse conditions, which plant strategies integrate predictability of biotic stress, and how such strategies can evolve. We propose that plants commonly optimise responses to correlated sequences or combinations of herbivores and pathogens, and that the predictability of these patterns is a key factor governing plant strategies in dynamic environments.</p

Establishment of environmentally sensitive DNA methylation states in the very early human embryo.

The molecular mechanisms responsible for the developmental origins of later disease are currently unknown. We previously demonstrated that women's periconceptional nutrition predicts their offspring's DNA methylation at metastable epialleles (MEs). We present a genome-wide screen yielding 687 MEs and track their trajectories across nine developmental stages in human in vitro fertilization embryos. MEs exhibit highly unusual methylation dynamics across the implantation-gastrulation transition, producing a large excess of intermediate methylation states, suggesting the potential for differential programming in response to external signals. Using a natural experiment in rural Gambia, we show that genomic regions sensitive to season of conception are highly enriched for MEs and show similar atypical methylation patterns. MEs are enriched for proximal enhancers and transcription start sites and are influenced by genotype. Together, these observations position MEs as distinctive epigenomic features programmed in the early embryo, sensitive to genetic and periconceptional environment, and with the potential to influence phenotype

Genomic properties of variably methylated retrotransposons in mouse

Abstract: Background: Transposable elements (TEs) are enriched in cytosine methylation, preventing their mobility within the genome. We previously identified a genome-wide repertoire of candidate intracisternal A particle (IAP) TEs in mice that exhibit inter-individual variability in this methylation (VM-IAPs) with implications for genome function. Results: Here we validate these metastable epialleles and discover a novel class that exhibit tissue specificity (tsVM-IAPs) in addition to those with uniform methylation in all tissues (constitutive- or cVM-IAPs); both types have the potential to regulate genes in cis. Screening for variable methylation at other TEs shows that this phenomenon is largely limited to IAPs, which are amongst the youngest and most active endogenous retroviruses. We identify sequences enriched within cVM-IAPs, but determine that these are not sufficient to confer epigenetic variability. CTCF is enriched at VM-IAPs with binding inversely correlated with DNA methylation. We uncover dynamic physical interactions between cVM-IAPs with low methylation ranges and other genomic loci, suggesting that VM-IAPs have the potential for long-range regulation. Conclusion: Our findings indicate that a recently evolved interplay between genetic sequence, CTCF binding, and DNA methylation at young TEs can result in inter-individual variability in transcriptional outcomes with implications for phenotypic variation

DNA methylation at a nutritionally sensitive region of the PAX8 gene is associated with thyroid volume and function in Gambian children.

Funder: Wellcome TrustPAX8 is a key thyroid transcription factor implicated in thyroid gland differentiation and function, and PAX8 gene methylation is reported to be sensitive to the periconceptional environment. Using a novel recall-by-epigenotype study in Gambian children, we found that PAX8 hypomethylation at age 2 years is associated with a 21% increase in thyroid volume and an increase in free thyroxine (T4) at 5 to 8 years, the latter equivalent to 8.4% of the normal range. Free T4 was associated with a decrease in DXA-derived body fat and bone mineral density. Furthermore, offspring PAX8 methylation was associated with periconceptional maternal nutrition, and methylation variability was influenced by genotype, suggesting that sensitivity to environmental exposures may be under partial genetic control. Together, our results demonstrate a possible link between early environment, PAX8 gene methylation and thyroid gland development and function, with potential implications for early embryonic programming of thyroid-related health and disease

Environmentally sensitive hotspots in the methylome of the early human embryo

In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin-specific methylation and germline differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental 'hotspots' providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease

Iron homeostasis in full-term, normal birthweight Gambian neonates over the first week of life

Human neonates elicit a profound hypoferremia which may protect against bacterial sepsis. We examined the transience of this hypoferremia by measuring iron and its chaperone proteins, inflammatory and haematological parameters over the first post-partum week. We prospectively studied term, normal weight Gambian newborns. Umbilical cord vein and artery, and serial venous blood samples up to day 7 were collected. Hepcidin, serum iron, transferrin, transferrin saturation, haptoglobin, c-reactive protein, α1-acid-glycoprotein, soluble transferrin receptor, ferritin, unbound iron-binding capacity and full blood count were assayed. In 278 neonates we confirmed the profound early postnatal decrease in serum iron (22.7 ± 7.0 µmol/L at birth to 7.3 ± 4.6 µmol/L during the first 6–24 h after birth) and transferrin saturation (50.2 ± 16.7% to 14.4 ± 6.1%). Both variables increased steadily to reach 16.5 ± 3.9 µmol/L and 36.6 ± 9.2% at day 7. Hepcidin increased rapidly during the first 24 h of life (19.4 ± 14.4 ng/ml to 38.9 ± 23.9 ng/ml) and then dipped (32.7 ± 18.4 ng/ml) before rising again at one week after birth (45.2 ± 19.1 ng/ml). Inflammatory markers increased during the first week of life. The acute postnatal hypoferremia in human neonates on the first day of life is highly reproducible but transient. The rise in serum iron during the first week of life occurs despite very high hepcidin levels indicating partial hepcidin resistance. Trial Registration: clinicaltrials.gov (NCT03353051). Registration date: November 27, 2017

Hepcidin mediates hypoferremia and reduces the growth potential of bacteria in the immediate post-natal period in human neonates.

Septicemia is a leading cause of death among neonates in low-income settings, a situation that is deteriorating due to high levels of antimicrobial resistance. Novel interventions are urgently needed. Iron stimulates the growth of most bacteria and hypoferremia induced by the acute phase response is a key element of innate immunity. Cord blood, which has high levels of hemoglobin, iron and transferrin saturation, has hitherto been used as a proxy for the iron status of neonates. We investigated hepcidin-mediated redistribution of iron in the immediate post-natal period and tested the effect of the observed hypoferremia on the growth of pathogens frequently associated with neonatal sepsis. Healthy, vaginally delivered neonates were enrolled in a cohort study at a single center in rural Gambia (N = 120). Cord blood and two further blood samples up to 96 hours of age were analyzed for markers of iron metabolism. Samples pooled by transferrin saturation were used to conduct ex-vivo growth assays with Staphylococcus aureus, Streptococcus agalactiae, Escherichia coli and Klebsiella pneumonia. A profound reduction in transferrin saturation occurred within the first 12 h of life, from high mean levels in cord blood (47.6% (95% CI 43.7-51.5%)) to levels at the lower end of the normal reference range by 24 h of age (24.4% (21.2-27.6%)). These levels remained suppressed to 48 h of age with some recovery by 96 h. Reductions in serum iron were associated with high hepcidin and IL-6 levels. Ex-vivo growth of all sentinel pathogens was strongly associated with serum transferrin saturation. These results suggest the possibility that the hypoferremia could be augmented (e.g. by mini-hepcidins) as a novel therapeutic option that would not be vulnerable to antimicrobial resistance. Trial registration: The original trial in which this study was nested is registered at ISRCTN, number 93854442

Magnetic Field Manipulation as a Means of Stabilization

Magnetic levitation technology is rapidly evolving, yet its applications to magnetic stabilization, or using magnetic levitation to stabilize a floating object, have not been fully explored. The goal of our research was to modify current magnetic levitation technology and create a proof-of-concept that paves the way for future research that more specifically explores the real-world applications of magnetic stabilization such as wind turbines. As such, our research was primarily focused on developing a system that could stabilize a levitating magnet using inductors. We accomplished this using data we gathered on several permanent magnets to ensure proper inductor calibration. We then developed code for a microcontroller with a real-time operating system to interface with the system's circuit components. We formulated the microcontroller's code by adapting a general control algorithm to make micro-adjustments to the current provided to our inductors. Our code used the real-time data gathered by a PCB Hall-effect sensor array to make the necessary adjustments to achieve stabilization and levitation. Our findings and methods for code development show encouraging results and suggest that further improvements to the design and calibration of our system should be explored in order to refine our proof-of-concept for specific applications

Respiratory infections drive hepcidin-mediated blockade of iron absorption leading to iron deficiency anemia in African children.

Iron deficiency anemia (IDA) is the most prevalent nutritional condition worldwide. We studied the contribution of hepcidin-mediated iron blockade to IDA in African children. We measured hepcidin and hemoglobin weekly, and hematological, inflammatory, and iron biomarkers at baseline, 7 weeks, and 12 weeks in 407 anemic (hemoglobin < 11 g/dl), otherwise healthy Gambian children (6 to 27 months). Each child maintained remarkably constant hepcidin levels (P < 0.0001 for between-child variance), with half consistently maintaining levels that indicate physiological blockade of iron absorption. Hepcidin was strongly predicted by nurse-ascribed adverse events with dominant signals from respiratory infections and fevers (all P < 0.0001). Diarrhea and fecal calprotectin were not associated with hepcidin. In multivariate analysis, C-reactive protein was the dominant predictor of hepcidin and contributed to iron blockade even at very low levels. We conclude that even low-grade inflammation, especially associated with respiratory infections, contributes to IDA in African children