Biology subjects

Youngson, N. A.

Publications and source records attributed to Youngson, N. A..

5 recordsLinked to original sources

bioRxiv2021

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease

The rate of nonalcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically-driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. Genome-wide histone acetylation is increased in steatotic livers of rodents fed high fructose or high fat diet. In vitro, steatosis relaxes chromatin and increases DNA damage marker {gamma}H2AX, which is reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and {gamma}H2AX are enriched at gene clusters in telomere-proximal regions which contain HCC tumor suppressors in hepatocytes and human fatty livers. Regions of metabolically-driven epigenetic change also have increased levels of DNA mutation in non-cancerous tissue from NAFLD patients. Finally, genome-scale network modelling indicates that redox balance is a key contributor to this mechanism. Thus abnormal histone hyperacetylation is a potential initiating event in HCC carcinogenesis.

cancer biology↗

bioRxiv2020

Ancestral dietary change alters development of Drosophila larvae through MAPK signalling

Increasing evidence in animal species ranging from mammals to insects has revealed phenotypes that are caused by ancestral life experiences including stress and diet. The descendent phenotypes themselves are wide ranging, and include changes to behaviour, disease risk, metabolism, and growth. Ancestral dietary macronutrient composition, and quantity (over- and under-nutrition) have been shown to alter descendent growth, metabolism and behaviour. Several studies have identified inherited molecules in gametes which are altered by ancestral diet and are required for the transgenerational effect. However, there is less understanding of the developmental pathways in the period between fertilisation and adulthood that are altered by the inherited molecules. Here we identify a key role of the MAPK signalling pathway in mediating changes to Drosophila larval developmental timing due to variation in ancestral diet. We exposed grand-parental and great grand-parental generations to defined protein to carbohydrate (P:C) dietary ratios and measured developmental timing. Descendent developmental timing was consistently faster in the period between the embryonic and pupal stages when the ancestor had a higher P:C ratio diet. Transcriptional analysis of embryos, larvae and adults revealed extensive and long-lasting changes to the MAPK signalling pathway which controlled growth rate through regulation of ribosomal RNA transcription. The importance of these processes was supported by pharmacological inhibition of MAPK and rRNA proteins which reproduced the ancestral diet-induced developmental changes. This work provides insight into the role of developmental growth signalling networks in mediating non-genetic inheritance in the period between fertilisation and adult. Summary statementAncestral, diet-induced descendent developmental timing changes are caused by alteration of MAPK signalling pathways in the period between the embryo and pupal stages in Drosophila.

developmental biology↗

bioRxiv2020

EXERCISE-INDUCED BENEFITS ON GLUCOSE HANDLING IN A MODEL OF DIET-INDUCED OBESITY ARE REDUCED BY CONCURRENT NICOTINAMIDE MONONUCLEOTIDE

ABSTRACTObjective Almost 40% of adults worldwide are classified as overweight or obese. Exercise is a beneficial intervention in obesity, partly due to increases in mitochondrial activity, with a potential role for the concomitant increase in nicotinamide adenine dinucleotide (NAD+). Recent studies have shown that increasing NAD+ levels through pharmacological supplementation with precursors such as nicotinamide mononucleotide (NMN) improved metabolic health in high fat diet (HFD) fed mice. We examined the combined effects of NMN and treadmill exercise on the metabolic dysregulation in HFD-induced obesity.Methods Five-week old female C57BL/6J mice were exposed to control diet or HFD. Mice fed HFD were treated with NMN in drinking water (400mg/kg; HNMN), treadmill exercise (HEx) or combined NMN and exercise (HNEx).Results Unexpectedly, NMN administration impaired several aspects of exercise-induced benefits in HFD mice, including glucose tolerance, glucose stimulated insulin secretion from islets and reduced hepatic triglyceride accumulation. Mechanistically, HNEx mice displayed increased antioxidant and reduced prooxidant gene expression in both islets and muscle, suggesting that altered redox status is associated with the loss of exercise-induced health benefits with NMN co-treatment.Conclusion Our data show that NMN treatment blocks the beneficial metabolic effects of exercise in a mouse model of diet-induced obesity in association with disturbances in redox metabolism.HighlightsNMN dampened exercise-induced benefits on glucose handling in diet-induced obesity.NMN administration in exercise enhanced ratio of antioxidants to prooxidants.We suggest NMN administration may not be beneficial when NAD+ levels are replete.Competing Interest StatementL.E.W. is an inventor on patents licensed to Metro Biotech NSW and to Jumpstart Fertility, and has received sponsored research funding from both companies. He is an advisor and shareholder in EdenRoc Sciences (Metro Biotech NSW, Metro Biotech, Liberty Biosecurity), Life Biosciences LLC and its daughter companies (Jumpstart Fertility, Continuum Biosciences, Senolytic Therapeutics, Selphagy, Animal Biosciences, Iduna) and in Intravital Pty Ltd. L.E.W. provides consulting work for Life Biosciences.View Full Text

physiology↗

bioRxiv2019

A natural antisense to brain-derived neurotrophic factor impairs extinction of drug seeking

BACKGROUNDBrain derived neurotrophic factor (BDNF) is critical for the extinction of drug-seeking. Expression of the Bdnf gene is highly regulated via interactions with non-coding RNA, which themselves are altered following drug exposure. Here we investigate whether a novel long non-coding RNA antisense to Bdnf prevents extinction of drug-seeking. METHODS: Strand-specific RNA sequencing identified a novel long non-coding RNA antisense to exon IV of the Bdnf gene in the ventromedial prefrontal cortex of 8 adult male rats. We then assessed asBdnf-IV expression using strand-specific reverse transcription and quantitative polymerase chain reaction following acquisition, extinction or abstinence from intravenous nicotine self-administration (N = 116). A functional role of the asBdnf-IV in extinction of nicotine-seeking was established by infusing gapmer oligonucleotides into the infralimbic cortex prior to extinction and testing for the effect of these infusions on reinstatement and reacquisition of nicotine-seeking (N = 36). RESULTSRNA sequencing identified the presence of a novel long non-coding RNA antisense to exon IV of the Bdnf gene (asBdnf-IV). Expression of asBdnf-IV was elevated following intravenous nicotine self-administration but not experimenter-administered nicotine. Elevated asBdnf-IV persisted across abstinence and to a greater extent following extinction training, suggesting an interaction between abstinence and extinction learning. In support of this, knockdown of the asBdnf-IV across extinction, but not abstinence, significantly attenuated nicotine-primed reinstatement of nicotine-seeking. CONCLUSIONSasBdnf-IV accumulates in the infralimbic cortex across self-administration training, interferes with the inhibitory learning that underpins extinction of drug-seeking, and predisposes animals to drug relapse.

neuroscience↗

bioRxiv2019

NAD+ repletion rescues female fertility during reproductive ageing

Female infertility is a common and devastating condition with life-long health, emotional and social consequences. There is currently no pharmacological therapy for preserving oocyte quality during aging, which is the strongest risk factor for infertility. This leads to an age dependent decline in natural conception and IVF success rates (1). Here, we show that this is due in part to declining levels of the metabolic cofactor nicotinamide adenine dinucleotide (NAD+), and that restoring NAD+ levels with its metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality and quantity in aged animals, leading to improved fertility. These benefits extend to the developing embryo, where NMN supplementation in embryo culture media following IVF enhances blastocyst formation in older mice. The NAD+ dependent deacylase SIRT2 is sufficient, but not essential, to recapitulate the benefits of in vivo NMN treatment, and transgenic overexpression of SIRT2 maintains oocyte spindle assembly, accurate chromosome segregation, decreased oxidative stress and overall fertility with ageing. Pharmacological elevation of NAD+ may be an effective, non-invasive strategy for restoring and maintaining female fertility during ageing, and for improving the success of IVF.

developmental biology↗