Fetal growth restriction in a genetic model of sporadic Beckwith–Wiedemann syndrome

Tunster, Simon James; Pette, Mathew Van de; Creeth, Hugo; Lefebvre, Louis; Roshan, John

doi:10.1242/dmm.035832

Cited by 7 publications

(5 citation statements)

References 59 publications

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“…2A) (Westerman et al, 2001;Miyamoto et al, 2002;Rentsendorj et al, 2010). Consistent with this hypothesis, the embryonic lethality of the aforementioned DelTel7 mouse model was partially rescued by restoring Ascl2 expression (Tunster et al, 2018).…”

Section: Pupd11 In Bwssupporting

confidence: 64%

Modeling human epigenetic disorders in mice: Beckwith-Wiedemann Syndrome and Silver-Russell Syndrome

Chang

Bartolomei

2020

Disease Models &Amp; Mechanisms

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Genomic imprinting, a phenomenon in which the two parental alleles are regulated differently, is observed in mammals, marsupials and a few other species, including seed-bearing plants. Dysregulation of genomic imprinting can cause developmental disorders such as Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). In this Review, we discuss (1) how various (epi)genetic lesions lead to the dysregulation of clinically relevant imprinted loci, and (2) how such perturbations may contribute to the developmental defects in BWS and SRS. Given that the regulatory mechanisms of most imprinted clusters are well conserved between mice and humans, numerous mouse models of BWS and SRS have been generated. These mouse models are key to understanding how mutations at imprinted loci result in pathological phenotypes in humans, although there are some limitations. This Review focuses on how the biological findings obtained from innovative mouse models explain the clinical features of BWS and SRS.

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Section: Pupd11 In Bwssupporting

confidence: 64%

Modeling human epigenetic disorders in mice: Beckwith-Wiedemann Syndrome and Silver-Russell Syndrome

Chang

Bartolomei

2020

Disease Models &Amp; Mechanisms

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“…ASCL2 (achaete-scute family bHLH transcription factor 2) is a member of the basic helix-loop-helix family of transcription factors, which are downstream targets of Wnt signaling [44], and it is involved in the determination of neuronal precursors in the peripheral and central nervous systems. Highly expressed in the skin, ASCL2 is associated with Beckwith-Wiedemann syndrome, which is the most common pediatric overgrowth syndrome [45]. Second, DMR hypermethylation and HLA-E gene expression upregulation were observed in W1 as compared to W0.…”

Section: Discussionmentioning

confidence: 99%

Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths

Spíndola¹,

Santoro²,

Pan³

et al. 2019

Clin Epigenet

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BackgroundPsychiatric symptomatology during late childhood and early adolescence tends to persist later in life. In the present longitudinal study, we aimed to identify changes in genome-wide DNA methylation patterns that were associated with the emergence of psychopathology in youths from the Brazilian High-Risk Cohort (HRC) for psychiatric disorders. Moreover, for the differentially methylated genes, we verified whether differences in DNA methylation corresponded to differences in mRNA transcript levels by analyzing the gene expression levels in the blood and by correlating the variation of DNA methylation values with the variation of mRNA levels of the same individuals. Finally, we examined whether the variations in DNA methylation and mRNA levels were correlated with psychopathology measurements over time.MethodsWe selected 24 youths from the HRC who presented with an increase in dimensional psychopathology at a 3-year follow-up as measured by the Child Behavior Checklist (CBCL). The DNA methylation and gene expression data were compared in peripheral blood samples (n = 48) obtained from the 24 youths before and after developing psychopathology. We implemented a methodological framework to reduce the effect of chronological age on DNA methylation using an independent population of 140 youths and the effect of puberty using data from the literature.ResultsWe identified 663 differentially methylated positions (DMPs) and 90 differentially methylated regions (DMRs) associated with the emergence of psychopathology. We observed that 15 DMPs were mapped to genes that were differentially expressed in the blood; among these, we found a correlation between the DNA methylation and mRNA levels of RB1CC1 and a correlation between the CBCL and mRNA levels of KMT2E. Of the DMRs, three genes were differentially expressed: ASCL2, which is involved in neurogenesis; HLA-E, which is mapped to the MHC loci; and RPS6KB1, the gene expression of which was correlated with an increase in the CBCL between the time points.ConclusionsWe observed that changes in DNA methylation and, consequently, in gene expression in the peripheral blood occurred concurrently with the emergence of dimensional psychopathology in youths. Therefore, epigenomic modulations might be involved in the regulation of an individual’s development of psychopathology.

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“…However, several examples show that they will help to understand specific clinical features in imprinting disorders, like growth disturbances, body fat composition or behavior (e.g. McNamara et al, 2016;van de Pette et al, 2016;Tunster et al, 2018).…”

Section: Clinical Spectrum Of Imprinting Disordersmentioning

confidence: 99%

Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences

Elbracht

Mackay

Begemann

et al. 2020

Human Reproduction Update

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BACKGROUND Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes. OBJECTIVE AND RATIONALE This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine. SEARCH METHODS Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms ‘multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction’ were used in various combinations. OUTCOMES A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders. WIDER IMPLICATIONS Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.

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Fetal growth restriction in a genetic model of sporadic Beckwith–Wiedemann syndrome

Cited by 7 publications

References 59 publications

Modeling human epigenetic disorders in mice: Beckwith-Wiedemann Syndrome and Silver-Russell Syndrome

Modeling human epigenetic disorders in mice: Beckwith-Wiedemann Syndrome and Silver-Russell Syndrome

Detecting multiple differentially methylated CpG sites and regions related to dimensional psychopathology in youths

Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences

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