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Article ; Online: Triiodothyronine (T3) Induces Limited Transcriptional and DNA Methylation Reprogramming in Human Monocytes

Rebecca Shepherd / Bowon Kim / Richard Saffery / Boris Novakovic

Biomedicines, Vol 10, Iss 608, p

2022 Volume 608

Abstract: Thyroid hormones have immunomodulatory roles, but their effects on the transcriptome and epigenome of innate immune cell types remain unexplored. In this study, we investigate the effects of triiodothyronine (T3) on the transcriptome and methylome of ... ...

Abstract	Thyroid hormones have immunomodulatory roles, but their effects on the transcriptome and epigenome of innate immune cell types remain unexplored. In this study, we investigate the effects of triiodothyronine (T3) on the transcriptome and methylome of human monocytes in vitro, both in resting and lipopolysaccharide (LPS)-stimulated conditions. In resting monocytes, 5 µM T3 affected the expression of a small number of monocyte-to-macrophage differentiation-associated genes, including TLR4 ( p -value < 0.05, expression fold change >1.5). T3 attenuated a small proportion of monocyte-to-macrophage differentiation-associated DNA methylation changes, while specifically inducing DNA methylation changes at several hundred differentially methylated CpG probes (DMPs) ( p -value < 0.05, Δβ > 0.05). In LPS-stimulated monocytes, the presence of T3 attenuated the effect of 27% of LPS-induced DMPs ( p -value < 0.05, Δβ > 0.05). Interestingly, co-stimulation with T3 + LPS induced a unique DNA methylation signature that was not observed in the LPS-only or T3-only exposure groups. Our results suggest that T3 induces limited transcriptional and DNA methylation remodeling in genes enriched in metabolism and immune processes and alters the normal in vitro LPS response. The overlap between differentially expressed genes and genes associated with DMPs was minimal; thus, other epigenetic mechanisms may underpin the expression changes. This research provides insight into the complex interplay between thyroid hormones, epigenetic remodeling, and transcriptional dynamics in monocytes.
Keywords	monocytes ; thyroid hormone ; T3 ; triiodothyronine ; DNA methylation ; transcriptome ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effect of an antenatal diet and lifestyle intervention and maternal BMI on cord blood DNA methylation in infants of overweight and obese women

Jennie Louise / Andrea R Deussen / Berthold Koletzko / Julie Owens / Richard Saffery / Jodie M Dodd

PLoS ONE, Vol 17, Iss 6, p e

The LIMIT Randomised Controlled Trial.

2022 Volume 0269723

Abstract: Background To investigate the effect of an antenatal diet and lifestyle intervention, and maternal pre-pregnancy overweight or obesity, on infant cord blood DNA methylation. Methods We measured DNA methylation in 645 cord blood samples from participants ... ...

Abstract	Background To investigate the effect of an antenatal diet and lifestyle intervention, and maternal pre-pregnancy overweight or obesity, on infant cord blood DNA methylation. Methods We measured DNA methylation in 645 cord blood samples from participants in the LIMIT study (an antenatal diet and lifestyle intervention for women with early pregnancy BMI ≥25.0 kg/m2) using the Illumina 450K BeadChip array, and tested for any differential methylation related to the intervention, and to maternal early pregnancy BMI. We also analysed differential methylation in relation to selected candidate genes. Results No CpG sites were significantly differentially methylated in relation to either the diet and lifestyle intervention, or with maternal early pregnancy BMI. There was no significant differential methylation in any of the selected genes related to the intervention, or to maternal BMI. Conclusion We found no evidence of an effect of either antenatal diet and lifestyle, or of maternal early pregnancy BMI, on cord blood DNA methylation. Clinical trials registration ACTRN12607000161426.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Potential for Novel Biomarkers in Diabetes-Associated Chronic Kidney Disease

Ashani Lecamwasam / Elif I. Ekinci / Richard Saffery / Karen M. Dwyer

Biomedicines, Vol 8, Iss 341, p

Epigenome, Metabolome, and Gut Microbiome

2020 Volume 341

Abstract: Diabetes-associated chronic kidney disease is a pandemic issue. Despite the global increase in the number of individuals with this chronic condition together with increasing morbidity and mortality, there are currently only limited therapeutic options to ...

Abstract	Diabetes-associated chronic kidney disease is a pandemic issue. Despite the global increase in the number of individuals with this chronic condition together with increasing morbidity and mortality, there are currently only limited therapeutic options to slow disease progression. One of the reasons for this is that the current-day “gold standard” biomarkers lack adequate sensitivity and specificity to detect early diabetic chronic kidney disease (CKD). This review focuses on the rapidly evolving areas of epigenetics, metabolomics, and the gut microbiome as potential sources of novel biomarkers in diabetes-associated CKD and discusses their relevance to clinical practice. However, it also highlights the problems associated with many studies within these three areas—namely, the lack of adequately powered longitudinal studies, and the lack of reproducibility of results which impede biomarker development and clinical validation in this complex and susceptible population.
Keywords	diabetes ; chronic kidney disease ; biomarker ; epigenetics ; metabolomics ; gut microbiome ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Increased maternal non-oxidative energy metabolism mediates association between prenatal di-(2-ethylhexyl) phthalate (DEHP) exposure and offspring autism spectrum disorder symptoms in early life

Sarah Thomson / Katherine Drummond / Martin O'Hely / Christos Symeonides / Chitra Chandran / Toby Mansell / Richard Saffery / Peter Sly / Jochen Mueller / Peter Vuillermin / Anne-Louise Ponsonby

Environment International, Vol 171, Iss , Pp 107678- (2023)

A birth cohort study

2023

Abstract: Prenatal phthalate exposure has previously been linked to the development of autism spectrum disorder (ASD). However, the underlying biological mechanisms remain unclear. We investigated whether maternal and child central carbon metabolism is involved as ...

Abstract	Prenatal phthalate exposure has previously been linked to the development of autism spectrum disorder (ASD). However, the underlying biological mechanisms remain unclear. We investigated whether maternal and child central carbon metabolism is involved as part of the Barwon Infant Study (BIS), a population-based birth cohort of 1,074 Australian children. We estimated phthalate daily intakes using third-trimester urinary phthalate metabolite concentrations and other relevant indices. The metabolome of maternal serum in the third trimester, cord serum at birth and child plasma at 1 year were measured by nuclear magnetic resonance. We used the Small Molecule Pathway Database and principal component analysis to construct composite metabolite scores reflecting metabolic pathways. ASD symptoms at 2 and 4 years were measured in 596 and 674 children by subscales of the Child Behavior Checklist and the Strengths and Difficulties Questionnaire, respectively. Multivariable linear regression analyses demonstrated (i) prospective associations between higher prenatal di-(2-ethylhexyl) phthalate (DEHP) levels and upregulation of maternal non-oxidative energy metabolism pathways, and (ii) prospective associations between upregulation of these pathways and increased offspring ASD symptoms at 2 and 4 years of age. Counterfactual mediation analyses indicated that part of the mechanism by which higher prenatal DEHP exposure influences the development of ASD symptoms in early childhood is through a maternal metabolic shift in pregnancy towards non-oxidative energy pathways, which are inefficient compared to oxidative metabolism. These results highlight the importance of the prenatal period and suggest that further investigation of maternal energy metabolism as a molecular mediator of the adverse impact of prenatal environmental exposures such as phthalates is warranted.
Keywords	Endocrine disrupting chemicals ; Metabolomics ; Pyruvate metabolism ; Warburg Effect ; Autism spectrum disorder ; Neurodevelopment ; Environmental sciences ; GE1-350
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Gut Microbiome Composition Remains Stable in Individuals with Diabetes-Related Early to Late Stage Chronic Kidney Disease

Ashani Lecamwasam / Tiffanie M. Nelson / Leni Rivera / Elif I. Ekinci / Richard Saffery / Karen M. Dwyer

Biomedicines, Vol 9, Iss 19, p

2021 Volume 19

Abstract: 1) Background: Individuals with diabetes and chronic kidney disease display gut dysbiosis when compared to healthy controls. However, it is unknown whether there is a change in dysbiosis across the stages of diabetic chronic kidney disease. We ... ...

Abstract	(1) Background: Individuals with diabetes and chronic kidney disease display gut dysbiosis when compared to healthy controls. However, it is unknown whether there is a change in dysbiosis across the stages of diabetic chronic kidney disease. We investigated a cross-sectional study of patients with early and late diabetes associated chronic kidney disease to identify possible microbial differences between these two groups and across each of the stages of diabetic chronic kidney disease. (2) Methods: This cross-sectional study recruited 95 adults. DNA extracted from collected stool samples were used for 16S rRNA sequencing to identify the bacterial community in the gut. (3) Results: The phylum Firmicutes was the most abundant and its mean relative abundance was similar in the early and late chronic kidney disease group, 45.99 ± 0.58% and 49.39 ± 0.55%, respectively. The mean relative abundance for family Bacteroidaceae, was also similar in the early and late group, 29.15 ± 2.02% and 29.16 ± 1.70%, respectively. The lower abundance of Prevotellaceae remained similar across both the early 3.87 ± 1.66% and late 3.36 ± 0.98% diabetic chronic kidney disease groups. (4) Conclusions: The data arising from our cohort of individuals with diabetes associated chronic kidney disease show a predominance of phyla Firmicutes and Bacteroidetes. The families Ruminococcaceae and Bacteroidaceae represent the highest abundance, while the beneficial Prevotellaceae family were reduced in abundance. The most interesting observation is that the relative abundance of these gut microbes does not change across the early and late stages of diabetic chronic kidney disease, suggesting that this is an early event in the development of diabetes associated chronic kidney disease. We hypothesise that the dysbiotic microbiome acquired during the early stages of diabetic chronic kidney disease remains relatively stable and is only one of many risk factors that influence progressive kidney dysfunction.
Keywords	chronic kidney disease ; diabetes ; dysbiosis ; gut microbiome ; microbiota ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Machine Learning SNP Based Prediction for Precision Medicine

Daniel Sik Wai Ho / William Schierding / Melissa Wake / Richard Saffery / Justin O’Sullivan

Frontiers in Genetics, Vol

2019 Volume 10

Abstract: In the past decade, precision genomics based medicine has emerged to provide tailored and effective healthcare for patients depending upon their genetic features. Genome Wide Association Studies have also identified population based risk genetic variants ...

Abstract	In the past decade, precision genomics based medicine has emerged to provide tailored and effective healthcare for patients depending upon their genetic features. Genome Wide Association Studies have also identified population based risk genetic variants for common and complex diseases. In order to meet the full promise of precision medicine, research is attempting to leverage our increasing genomic understanding and further develop personalized medical healthcare through ever more accurate disease risk prediction models. Polygenic risk scoring and machine learning are two primary approaches for disease risk prediction. Despite recent improvements, the results of polygenic risk scoring remain limited due to the approaches that are currently used. By contrast, machine learning algorithms have increased predictive abilities for complex disease risk. This increase in predictive abilities results from the ability of machine learning algorithms to handle multi-dimensional data. Here, we provide an overview of polygenic risk scoring and machine learning in complex disease risk prediction. We highlight recent machine learning application developments and describe how machine learning approaches can lead to improved complex disease prediction, which will help to incorporate genetic features into future personalized healthcare. Finally, we discuss how the future application of machine learning prediction models might help manage complex disease by providing tissue-specific targets for customized, preventive interventions.
Keywords	machine learning ; polygenic risk score ; precision medicine ; genetic disease risk prediction ; personalized medicine ; complex disease risk ; Genetics ; QH426-470
Subject code	006
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mass cytometry analysis of blood from peanut-sensitized tolerant and clinically allergic infants

Amanda R. Tursi / Nicholas K. Saba / Diane Dunham / Monali Manohar / Rachel L. Peters / Richard Saffery / Jennifer J. Koplin / Kari C. Nadeau / Melanie R. Neeland / Sandra Andorf

Scientific Data, Vol 9, Iss 1, Pp 1-

2022 Volume 8

Abstract: Measurement(s) expression profiling Technology Type(s) cytometry time of flight assay Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location ... ...

Abstract	Measurement(s) expression profiling Technology Type(s) cytometry time of flight assay Sample Characteristic - Organism Homo sapiens Sample Characteristic - Location Australia
Keywords	Science ; Q
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Metabolic Signatures of Surviving Cotwins in Cases of Single Intrauterine Fetal Death During Monochorionic Diamniotic Pregnancy

Xiyao Liu / Huijia Fu / Li Wen / Fangyu Zhu / Yue Wu / Zhi Chen / Richard Saffery / Chang Chen / Hongbo Qi / Chao Tong / Philip N. Baker / Mark D. Kilby

Frontiers in Molecular Biosciences, Vol

A Prospective Case-Control Study

2022 Volume 9

Abstract: Introduction: Single intrauterine fetal death (sIUFD) in monochorionic diamniotic (MCDA) twin pregnancy may be associated with adverse clinical outcomes and possible metabolic changes in the surviving co-twin. Metabolomic profiling has not been ... ...

Abstract	Introduction: Single intrauterine fetal death (sIUFD) in monochorionic diamniotic (MCDA) twin pregnancy may be associated with adverse clinical outcomes and possible metabolic changes in the surviving co-twin. Metabolomic profiling has not been undertaken before in these complex twin pregnancies.Methods: In this prospectively collected case-control study, three cross-cohort comparisons were made between sIUFD MCDA (n = 16), uncomplicated MCDA (n = 16, eight pairs), and uncomplicated singleton pregnancies (n = 8). To identify major sources of variation within the sIUFD MCDA cohort, a secondary comparison was conducted between spontaneous sIUFD (n = 8) and sIUFD in MCDA twins due to selective termination of a single abnormal fetus by radiofrequency ablation (RFA) (n = 8). Metabolomics analysis of placental tissue and umbilical cord plasma was performed using LC-MS profiling. The underlying metabolic networks and pathways were analyzed by web-based platforms. Associations and statistical correlations of all identified differential metabolites with neonatal birthweight and birth length were assessed by multivariable linear regression, adjusted for maternal age and gestation.Results: Across four comparisons, 131 and 111 differential metabolites were identified in placental tissue and cord plasma, respectively, with the highest variation seen between the spontaneous vs. single-induced IUFD in MCDA twins by RFA in the cord plasma. Conversely, the number of viable fetuses and the presence of sIUFD in MCDA twins had the highest impact on metabolite variation in placental tissue. Compounds correlated with fetal growth including placental acylcarnitines and gangliosides, along with specific amino acids (e.g., histidinyl-hydroxyproline), xenobiotics and biliverdin in cord plasma.Conclusion: sIUFD in MCDA twin pregnancy correlates with distinctive metabolic signatures, mostly in fatty acyls and complex lipids, in placental tissue and cord plasma of the surviving cotwin. Some metabolites are also associated with fetal growth.
Keywords	LC-MS ; maternal-fetal interface ; metabolites ; metabolome ; radiofrequency ablation ; spontaneous fetal death ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Distinct Role of the HDL Receptor SR-BI in Cholesterol Homeostasis of Human Placental Arterial and Venous Endothelial Cells

Manuela Strahlhofer-Augsten / Carolin Schliefsteiner / Silvija Cvitic / Meekha George / Ingrid Lang-Olip / Birgit Hirschmugl / Gunther Marsche / Uwe Lang / Boris Novakovic / Richard Saffery / Gernot Desoye / Christian Wadsack

International Journal of Molecular Sciences, Vol 23, Iss 5364, p

2022 Volume 5364

Abstract: As opposed to adults, high-density lipoprotein (HDL) is the main cholesterol carrying lipoprotein in fetal circulation. The major HDL receptor, scavenger receptor class B type I (SR-BI), contributes to local cholesterol homeostasis. Arterial endothelial ... ...

Abstract	As opposed to adults, high-density lipoprotein (HDL) is the main cholesterol carrying lipoprotein in fetal circulation. The major HDL receptor, scavenger receptor class B type I (SR-BI), contributes to local cholesterol homeostasis. Arterial endothelial cells (ECA) from human placenta are enriched with cholesterol compared to venous endothelial cells (ECV). Moreover, umbilical venous and arterial plasma cholesterol levels differ markedly. We tested the hypothesis that the uptake of HDL-cholesteryl esters differs between ECA and ECV because of the differential expression of SR-BI. We aimed to identify the key regulators underlying these differences and the functional consequences. Immunohistochemistry was used for visualization of SR-BI in situ. ECA and ECV were isolated from the chorionic plate of human placenta and used for RT-qPCR, Western Blot, and HDL uptake assays with 3 H- and 125 I-labeled HDL. DNA was extracted for the methylation profiling of the SR-BI promoter. SR-BI regulation was studied by exposing ECA and ECV to differential oxygen concentrations or shear stress. Our results show elevated SR-BI expression and protein abundance in ECA compared to ECV in situ and in vitro. Immunohistochemistry demonstrated that SR-BI is mainly expressed on the apical side of placental endothelial cells in situ, allowing interaction with mature HDL circulating in the fetal blood. This was functionally linked to a higher increase of selective cholesterol ester uptake from fetal HDL in ECA than in ECV, and resulted in increased cholesterol availability in ECA. SR-BI expression on ECV tended to decrease with shear stress, which, together with heterogeneous immunostaining, suggests that SR-BI expression is locally regulated in the placental vasculature. In addition, hypomethylation of several CpG sites within the SR-BI promoter region might contribute to differential expression of SR-BI between chorionic arteries and veins. Therefore, SR-BI contributes to a local cholesterol homeostasis in ECA and ECV of the human ...
Keywords	human placenta ; SR-BI ; HDL ; endothelium ; arterial-venous difference ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Crucial timing in schizophrenia: role of DNA methylation in early neurodevelopment

Ryan, Joanne / Richard Saffery

Genome biology. 2014 Oct., v. 15, no. 10

2014

Abstract: An exciting recent study examining the methylation profile of human brain tissue implicates early-life epigenetic disruption in the neurodevelopmental origin of schizophrenia.See related research, http://genomebiology.com/2014/15/10/ ... ...

Abstract	An exciting recent study examining the methylation profile of human brain tissue implicates early-life epigenetic disruption in the neurodevelopmental origin of schizophrenia.See related research, http://genomebiology.com/2014/15/10/483
Keywords	brain ; DNA methylation ; epigenetics ; humans ; neurodevelopment ; schizophrenia
Language	English
Dates of publication	2014-10
Size	p. 495.
Publishing place	Springer-Verlag
Document type	Article
ZDB-ID	2040529-7
ISSN	1474-760X ; 1465-6914 ; 1465-6906
ISSN (online)	1474-760X ; 1465-6914
ISSN	1465-6906
DOI	10.1186/s13059-014-0495-y
Database	NAL-Catalogue (AGRICOLA)

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