Epigenetic and genetic variation at the<i>IGF2/H19</i>imprinting control region on 11p15.5 is associated with cerebellum weight

Pidsley, Ruth; Dempster, Emma; Troakes, Claire; Al‐Sarraj, Safa; Mill, Jonathan

doi:10.4161/epi.7.2.18910

Cited by 32 publications

(24 citation statements)

References 68 publications

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“…Igf2 is imprinted in the rodent neonatal granule cells of the cerebellar parenchyma but not in the adult choroid plexus and leptomeninges (DeChiara et al, 1991;Pedone et al, 1994;Hetts et al, 1997). The expression in the granule cells has been associated with a role in cell proliferation and cerebellum weight during fetal and neonatal development (Hetts et al, 1997;Fernandez et al, 2010;Pidsley et al, 2012). In humans, IGF2 is monoallelically expressed within specific regions of the adult brain while it is biallelic in the fetal brain (Pham et al, 1998).…”

Section: The Evolution Of Imprinting In the Post-natal Mammalmentioning

confidence: 99%

“…Therefore, regionally restricted imprinting of IGF2 in the brain of human, mouse and tammar (Hetts et al, 1997;Suzuki et al, 2005;Smits et al, 2008;Stringer et al, 2012b) suggests that this pattern may have evolved in the therian ancestor. In the brain, IGF2 has been implicated in the regulation of brain morphology, food intake and in memory consolidation and enhancement (Lauterio et al, 1987;Ahmed and Lauterio, 1992;Hetts et al, 1997;Fernandez et al, 2010;Chen et al, 2011;Pidsley et al, 2012). In the adult rat, intracerebroventricular injection of IGF2 decreases food intake while injections into the hippocampus can significantly enhance memory retention.…”

Section: The Evolution Of Imprinting In the Post-natal Mammalmentioning

confidence: 99%

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Post-natal imprinting: evidence from marsupials

et al. 2014

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Genomic imprinting has been identified in therian (eutherian and marsupial) mammals but not in prototherian (monotreme) mammals. Imprinting has an important role in optimising pre-natal nutrition and growth, and most imprinted genes are expressed and imprinted in the placenta and developing fetus. In marsupials, however, the placental attachment is short-lived, and most growth and development occurs post-natally, supported by a changing milk composition tailor-made for each stage of development. Therefore there is a much greater demand on marsupial females during post-natal lactation than during pre-natal placentation, so there may be greater selection for genomic imprinting in the mammary gland than in the short-lived placenta. Recent studies in the tammar wallaby confirm the presence of genomic imprinting in nutrient-regulatory genes in the adult mammary gland. This suggests that imprinting may influence infant post-natal growth via the mammary gland as it does pre-natally via the placenta. Similarly, an increasing number of imprinted genes have been implicated in regulating feeding and nurturing behaviour in both the adult and the developing neonate/offspring in mice. Together these studies provide evidence that genomic imprinting is critical for regulating growth and subsequently the survival of offspring not only pre-natally but also post-natally.

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Section: The Evolution Of Imprinting In the Post-natal Mammalmentioning

confidence: 99%

Section: The Evolution Of Imprinting In the Post-natal Mammalmentioning

confidence: 99%

Post-natal imprinting: evidence from marsupials

et al. 2014

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“…The key role of the IGF axis and methylation of its related genes in head size maintenance is evident; for example, IGF1 -deficient subjects treated with exogenous IGF1 show a striking increase in head circumference [52]. Adult brain size has been shown to relate positively to IGF2 DMR2 (exon 9) methylation and be negatively related to IGF / H19 ICR (at the CTCF3 region 2kb from our ICR assay) DNA methylation in DNA extracted from the cerebellum [53,54]. Although the region within the ICR assayed in the latter study did not overlap with our assay, the negative direction of association was the same.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults

et al. 2012

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BackgroundThe insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity.DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression.ResultsThe principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC.ConclusionsAs greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required.

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“…Epigenetic and environmental influences are also likely to contribute substantially to cerebellar disease burden and psychiatric diseases linked to cerebellar dysfunction. Investigative studies in the laboratory, aimed at unraveling the potential mechanisms whereby alterations that affect development through means other than changes in the coding sequences of genes cause disease are just beginning and represent an important piece of the puzzle (Pidsley et al, 2012; James et al, 2013). …”

Section: Future Directionsmentioning

confidence: 99%

Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences

Basson¹,

Wingate²

2013

Front. Neuroanat.

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Over the last 60 years, the spotlight of research has periodically returned to the cerebellum as new techniques and insights have emerged. Because of its simple homogeneous structure, limited diversity of cell types and characteristic behavioral pathologies, the cerebellum is a natural home for studies of cell specification, patterning, and neuronal migration. However, recent evidence has extended the traditional range of perceived cerebellar function to include modulation of cognitive processes and implicated cerebellar hypoplasia and Purkinje neuron hypo-cellularity with autistic spectrum disorder. In the light of this emerging frontier, we review the key stages and genetic mechanisms behind cerebellum development. In particular, we discuss the role of the midbrain hindbrain isthmic organizer in the development of the cerebellar vermis and the specification and differentiation of Purkinje cells and granule neurons. These developmental processes are then considered in relation to recent insights into selected human developmental cerebellar defects: Joubert syndrome, Dandy–Walker malformation, and pontocerebellar hypoplasia. Finally, we review current research that opens up the possibility of using the mouse as a genetic model to study the role of the cerebellum in cognitive function.

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Epigenetic and genetic variation at theIGF2/H19imprinting control region on 11p15.5 is associated with cerebellum weight

Cited by 32 publications

References 68 publications

Post-natal imprinting: evidence from marsupials

Post-natal imprinting: evidence from marsupials

DNA methylation of the IGF2/H19 imprinting control region and adiposity distribution in young adults

Congenital hypoplasia of the cerebellum: developmental causes and behavioral consequences

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