Preterm Birth and the Risk of Neurodevelopmental Disorders - Is There a Role for Epigenetic Dysregulation?

Fitzgerald, Eamon; Boardman, James P.; Drake, Amanda J.

doi:10.2174/1389202919666171229144807

Cited by 34 publications

(28 citation statements)

References 191 publications

(208 reference statements)

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“…The site has strong evidence of long-term evolutionary conservation. The gene TET3 has been shown to be elevated in preeclamptic and small for gestational age (SGA) placentas 53 . The rs6546894 variant is also associated with changes in expression of genes MGC10955 and NAT8 in the testis (TST), brain (BRN), uterus (UTR), ovaries (OVR), and vagina (VGN) tissues.…”

Section: Resultsmentioning

confidence: 99%

“…Expression profiling showed elevated TET3 transcripts in preeclamptic placentas and in pregnancies ending with the birth of a newborn that is small for gestational age (SGA) 52 . TET3 is also hypothesized to play a role in the link between preterm birth and the risk of neurodevelopmental disorders due to the gene’s role in epigenetic regulation 53 . NAT8 , which is involved in acetylation of histones, may also play a role in epigenetic changes during pregnancy 54 .…”

Section: Resultsmentioning

confidence: 99%

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Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

LaBella

Abraham

Pichkar

et al. 2019

Preprint

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35Human pregnancy requires the coordinated function of multiple tissues in both mother and fetus and has 36 evolved in concert with major human adaptations. As a result, pregnancy-associated phenotypes and 37 related disorders are genetically complex and have likely been sculpted by diverse evolutionary forces. 38 However, there is no framework to comprehensively evaluate how these traits evolved or to explore the 39 relationship of evolutionary signatures on trait-associated genetic variants to molecular function. Here we 40develop an approach to test for signatures of diverse evolutionary forces, including multiple types of 41 selection, and apply it to genomic regions associated with spontaneous preterm birth (sPTB), a complex 42 disorder of global health concern. We find that sPTB-associated regions harbor diverse evolutionary 43 signatures including evolutionary sequence conservation (consistent with the action of negative selection), 44 excess population differentiation (local adaptation), accelerated evolution (positive selection), and 45 balanced polymorphism (balancing selection). Furthermore, these genomic regions show diverse 46 functional characteristics which enables us to use evolutionary and molecular lines of evidence to develop 47 54Mammalian pregnancy requires the coordination of multiple maternal and fetal tissues 1,2 and extensive 55 modulation of the maternal immune system so that the genetically distinct fetus is not immunologically 56 rejected 3 . Given this context, pregnancy-related phenotypes and disorders are likely to have experienced 57 diverse selective pressures. This is particularly likely on the human lineage where pregnancy has been 58 shaped by unique human adaptations such as bipedality and enlarged brain size 4-8 . One major disorder of 59 pregnancy is preterm birth (PTB), a complex multifactorial syndrome 9 that affects 10% of pregnancies in 60 the United States and more than 15 million pregnancies worldwide each year 10,11 . PTB leads to increased 61 infant mortality rates and significant short-and long-term morbidity [11][12][13][14] . Risk for PTB varies 62 substantially with race, environment, comorbidities, and genetic factors 15 . PTB is broadly classified into 63 iatrogenic PTB, when it is associated with medical conditions such as preeclampsia (PE) or intrauterine 64 growth restriction (IUGR), and spontaneous PTB (sPTB), which occurs in the absence of preexisting 65 medical conditions or is initiated by preterm premature rupture of membranes [16][17][18][19] . The biological 66 pathways contributing to sPTB remain poorly understood 9 , but diverse lines of evidence suggest that 67 maternal genetic variation is an important contributor 20-24 . 68The complexity of human pregnancy and association with unique human adaptations raise the hypothesis 69 that genetic variants associated with birth timing and sPTB have been shaped by diverse evolutionary 70 forces. Consistent with this hypothesis, several immune genes involved in pregnancy have signatures of 71 recent purifyin...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

LaBella

Abraham

Pichkar

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…This may also have relevance for preterm birth, indeed we have shown alterations in DNA methylation at key neurodevelopmental loci in buccal cells of infants born preterm, which were taken at term equivalent age [22]. A number of further studies have reported differences in DNA methylation between preterm and term infants at birth [23][24][25][26] although the extent to which these are persistent is unclear [25,[27][28][29]. To better understand the relative influence of potential stressors associated with PTB, and to dissect underlying mechanisms, including epigenetic dysregulation in the tissue of interest, a number of animal models have been used [30].…”

Section: Introductionmentioning

confidence: 86%

Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress

Fitzgerald

Sinton

Wernig-Zorc

et al. 2020

Preprint

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Early life stress during childhood is associated with a number of psychiatric disorders that manifest across the life course. Preterm birth is a profound stressor, and an important cause of cognitive impairment, as well as neurodevelopmental and psychiatric disorders. However, the mechanisms that link events during the early neonatal period with later functional problems are poorly understood. We developed a novel mouse model of early life stress (modified maternal separation; MMS) with specific relevance to preterm birth (PTB) and hypothesised it would affect the hypothalamic transcriptome and DNA methylome and impact on behaviour in adulthood. MMS consisted of repeatedly stimulating pups for 1.5 hours/day, whilst separated from their mother, from postnatal day (P)4-6. 3' RNA sequencing and DNA methylation immunoprecipitation (meDIP) sequencing was performed on the hypothalamus at P6. Behaviour was assessed with the elevated plus and open field mazes, and in-cage monitoring at 3-4 months of age. Although MMS was only associated with subtle changes in gene expression there were widespread alterations in DNA methylation. Notably, differentially methylated regions were enriched for synapse-associated loci. MMS also resulted in hyperactivity in the elevated plus and open field mazes, but in-cage monitoring revealed that this was not representative of habitual hyperactivity. In conclusion we describe a novel model of early life stress with relevance to PTB, with marked effects on DNA methylation in the hypothalamus and with stress-specific hyperactivity in young adulthood. We suggest that these results have implications for the understanding of early life stress mediated effects on brain development.

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“…Preterm birth complications are a leading cause of under-five mortality, causing more than one million deaths per year (3). In addition to the much higher mortality risk, children born preterm face higher rates of neurodevelopmental disability as well as delays in their physical and cognitive abilities more generally (4)(5)(6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…African Population and Health Research Center, Manga Close, P.O BOX 10787, 00100, Nairobi, Kenya 4. University of São Paulo Medical School, Av.…”

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confidence: 99%

Kangaroo Mother Care for Preterm Infants and Child Development – Evidence from São Paulo, Brazil

Onyango

Brentani

Fink

2019

Preprint

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Background An estimated 15 million children are born prematurely each year globally, resulting in a high burden of under-five mortality and neurodevelopmental disability. Kangaroo Mother Care (KMC) is recognized as key intervention to support the development of preterm infants. Even though the benefits of KMC have been well documented in randomized controlled trials, evidence on the impact of KMC in routine care settings remains limited.Methods This paper examines the associations between maternal Kangaroo Mother Care efforts and child development among preterm infants born at the University Hospital of São Paulo, Brazil. Primary study outcomes were physical development (HAZ) and cognitive development at age 3.Results Practicing Kangaroo Mother Care was positively associated with physical development (+0.91 SD, 95% confidence intervals [0.126, 1.695]), and cognition (+0.37 SD, [0.034, 0.806]) of preterm children at age 3.Conclusion The results presented suggest that KMC has a large potential to improve children’s cognitive and physical development. New programs to increase KMC uptake in the setting studied may be beneficial for both mothers and their preterm children.

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Preterm Birth and the Risk of Neurodevelopmental Disorders - Is There a Role for Epigenetic Dysregulation?

Cited by 34 publications

References 191 publications

Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

Accounting for diverse evolutionary forces reveals the mosaic nature of selection on genomic regions associated with human preterm birth

Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress

Kangaroo Mother Care for Preterm Infants and Child Development – Evidence from São Paulo, Brazil

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