MAI KA PIKO A KE MOLE: CLEARING PATHS AND INSPIRING JOURNEYS TO FULFILL KULEANA THROUGH ʻĀINA EDUCATION

Ph.D

Inherent promoter bidirectionality facilitates maintenance of sequence integrity and transcription of parasitic DNA in mammalian genomes

<p>Abstract</p> <p>Background</p> <p>Many mammalian genes are arranged in a bidirectional manner, sharing a common promoter and regulatory elements. This is especially true for promoters containing a CpG island, usually unmethylated and associated with an 'open' or accessible chromatin structure. In evolutionary terms, a primary function of genomic methylation is postulated to entail protection of the host genome from the disruption associated with activity of parasitic or transposable elements. These are usually epigenetically silenced following insertion into mammalian genomes, becoming sequence degenerate over time. Despite this, it is clear that many transposable element-derived DNAs have evaded host-mediated epigenetic silencing to remain expressed (domesticated) in mammalian genomes, several of which have demonstrated essential roles during mammalian development.</p> <p>Results</p> <p>The current study provides evidence that many CpG island-associated promoters associated with single genes exhibit inherent bidirectionality, facilitating "hijack" by transposable elements to create novel antisense 'head-to-head' bidirectional gene pairs in the genome that facilitates escape from host-mediated epigenetic silencing. This is often associated with an increase in CpG island length and transcriptional activity in the antisense direction. From a list of over 60 predicted protein-coding genes derived from transposable elements in the human genome and 40 in the mouse, we have found that a significant proportion are orientated in a bidirectional manner with CpG associated regulatory regions.</p> <p>Conclusion</p> <p>These data strongly suggest that the selective force that shields endogenous CpG-containing promoter from epigenetic silencing can extend to exogenous foreign DNA elements inserted in close proximity in the antisense orientation, with resulting transcription and maintenance of sequence integrity of such elements in the host genome. Over time, this may result in "domestication" of such elements to provide novel cellular and developmental functions.</p

Human transgenerational responses to early-life experience:potential impact on development, health and biomedical research

Mammalian experiments provide clear evidence of male line transgenerational effects on health and development from paternal or ancestral early-life exposures such as diet or stress. The few human observational studies to date suggest (male line) transgenerational effects exist that cannot easily be attributed to cultural and/or genetic inheritance. Here we summarise relevant studies, drawing attention to exposure sensitive periods in early life and sex differences in transmission and offspring outcomes. Thus, variation, or changes, in the parental/ancestral environment may influence phenotypic variation for better or worse in the next generation(s), and so contribute to common, non-communicable disease risk including sex differences. We argue that life-course epidemiology should be reframed to include exposures from previous generations, keeping an open mind as to the mechanisms that transmit this information to offspring. Finally, we discuss animal experiments, including the role of epigenetic inheritance and non-coding RNAs, in terms of what lessons can be learnt for designing and interpreting human studies. This review was developed initially as a position paper by the multidisciplinary Network in Epigenetic Epidemiology to encourage transgenerational research in human cohorts

Maternal prenatal mental health and placental 11β-HSD2 gene expression: initial findings from the mercy pregnancy and emotional wellbeing study

High intrauterine cortisol exposure can inhibit fetal growth and have programming effects for the child\u27s subsequent stress reactivity. Placental 11beta-hydroxysteroid dehydrogenase (11&beta;-HSD2) limits the amount of maternal cortisol transferred to the fetus. However, the relationship between maternal psychopathology and 11&beta;-HSD2 remains poorly defined. This study examined the effect of maternal depressive disorder, antidepressant use and symptoms of depression and anxiety in pregnancy on placental 11&beta;-HSD2 gene (HSD11B2) expression. Drawing on data from the Mercy Pregnancy and Emotional Wellbeing Study, placental HSD11B2 expression was compared among 33 pregnant women, who were selected based on membership of three groups; depressed (untreated), taking antidepressants and controls. Furthermore, associations between placental HSD11B2 and scores on the State-Trait Anxiety Inventory (STAI) and Edinburgh Postnatal Depression Scale (EPDS) during 12-18 and 28-34 weeks gestation were examined. Findings revealed negative correlations between HSD11B2 and both the EPDS and STAI (r = -0.11 to -0.28), with associations being particularly prominent during late gestation. Depressed and antidepressant exposed groups also displayed markedly lower placental HSD11B2 expression levels than controls. These findings suggest that maternal depression and anxiety may impact on fetal programming by down-regulating HSD11B2, and antidepressant treatment alone is unlikely to protect against this effect

Intrauterine programming of obesity and type 2 diabetes

Abstract: The type 2 diabetes epidemic and one of its predisposing factors, obesity, are major influences on global health and economic burden. It is accepted that genetics and the current environment contribute to this epidemic; however, in the last two decades, both human and animal studies have consolidated considerable evidence supporting the ‘developmental programming’ of these conditions, specifically by the intrauterine environment. Here, we review the various in utero exposures that are linked to offspring obesity and diabetes in later life, including epidemiological insights gained from natural historical events, such as the Dutch Hunger Winter, the Chinese famine and the more recent Quebec Ice Storm. We also describe the effects of gestational exposure to endocrine disruptors, maternal infection and smoking to the fetus in relation to metabolic programming. Causal evidence from animal studies, motivated by human observations, is also discussed, as well as some of the proposed underlying molecular mechanisms for developmental programming of obesity and type 2 diabetes, including epigenetics (e.g. DNA methylation and histone modifications) and microRNA interactions. Finally, we examine the effects of non-pharmacological interventions, such as improving maternal dietary habits and/or increasing physical activity, on the offspring epigenome and metabolic outcomes

Australian parental perceptions of genomic newborn screening for non-communicable diseases

Background: Newborn bloodspot screening (NBS) programs have improved neonatal healthcare since the 1960s. Genomic sequencing now offers potential to generate polygenic risk score (PRS) that could be incorporated into NBS programs, shifting the focus from treatment to prevention of future noncommunicable disease (NCD). However, Australian parents’ knowledge and attitudes regarding PRS for NBS is currently unknown.Methods: Parents with at least one Australian-born child under 18 years were invited via social media platforms to complete an online questionnaire aimed at examining parents’ knowledge of NCDs, PRS, and precision medicine, their opinions on receiving PRS for their child, and considerations of early-intervention strategies to prevent the onset of disease.Results: Of 126 participants, 90.5% had heard the term “non-communicable disease or chronic condition,” but only 31.8% and 34.4% were aware of the terms “polygenic risk score” and “precision medicine” respectively. A large proportion of participants said they would consider screening their newborn to receive a PRS for allergies (77.9%), asthma (81.0%), cancer (64.8%), cardiovascular disease (65.7%), mental illness (56.7%), obesity (49.5%), and type 2 diabetes (66.7%). Additionally, participants would primarily consider diet and exercise as interventions for specific NCDs.Discussion: The results from this study will inform future policy for genomic NBS, including expected rate of uptake and interventions that parents would consider employing to prevent the onset of disease

Evaluation of microRNA expression in patient bone marrow aspirate slides

<div><p>Like formalin fixed paraffin embedded (FFPE) tissues, archived bone marrow aspirate slides are an abundant and untapped resource of biospecimens that could enable retrospective molecular studies of disease. Historically, RNA obtained from slides is limited in utility because of their low quality and highly fragmented nature. MicroRNAs are small (≈22 nt) non-coding RNA that regulate gene expression, and are speculated to preserve well in FFPE tissue. Here we investigate the use of archived bone marrow aspirate slides for miRNA expression analysis in paediatric leukaemia. After determining the optimal method of miRNA extraction, we used TaqMan qRT-PCR to identify reference miRNA for normalisation of other miRNA species. We found hsa-miR-16 and hsa-miR-26b to be the most stably expressed between lymphoblastoid cell lines, primary bone marrow aspirates and archived samples. We found the average fold change in expression of hsa-miR-26b and two miRNA reportedly dysregulated in leukaemia (hsa-miR-128a, hsa-miR-223) was <0.5 between matching archived slide and bone marrow aspirates. Differential expression of hsa-miR-128a and hsa-miR-223 was observed between leukaemic and non-leukaemic bone marrow from archived slides or flash frozen bone marrow. The demonstration that archived bone marrow aspirate slides can be utilized for miRNA expression studies offers tremendous potential for future investigations into the role miRNA play in the development and long term outcome of hematologic, as well as non-hematologic, diseases.</p> </div

Stress-sensitive neurosignalling in depression : an integrated network biology approach to candidate gene selection for genetic association analysis

Genetic risk for depressive disorders is poorly understood despite consistent suggestions of a high heritable component. Most genetic studies have focused on risk associated with single variants, a strategy which has so far only yielded small (often non-replicable) risks for depressive disorders. In this paper we argue that more substantial risks are likely to emerge from genetic variants acting in synergy within and across larger neurobiological systems (polygenic risk factors). We show how knowledge of major integrated neurobiological systems provides a robust basis for defining and testing theoretically defensible polygenic risk factors. We do this by describing the architecture of the overall stress response. Maladaptation via impaired stress responsiveness is central to the aetiology of depression and anxiety and provides a framework for a systems biology approach to candidate gene selection. We propose principles for identifying genes and gene networks within the neurosystems involved in the stress response and for defining polygenic risk factors based on the neurobiology of stress-related behaviour. We conclude that knowledge of the neurobiology of the stress response system is likely to play a central role in future efforts to improve genetic prediction of depression and related disorders