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

Chang, Suhee; Bartolomei, Marisa S.

doi:10.1242/dmm.044123

Cited by 35 publications

(29 citation statements)

References 145 publications

(174 reference statements)

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“…or ICRs are used as models for human imprinting diseases such as Prader-Willi, Angelman, Beckwith-Wiedemann, and Silver-Russell syndromes (Chang and Bartolomei, 2020). However, orthologs of non-canonical imprinted genes are not likely to be imprinted in humans.…”

Section: Canonical and Non-canonical Imprinting In The Other Rodentsmentioning

confidence: 99%

Canonical and Non-canonical Genomic Imprinting in Rodents

Kobayashi

2021

Front. Cell Dev. Biol.

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Genomic imprinting is an epigenetic phenomenon that results in unequal expression of homologous maternal and paternal alleles. This process is initiated in the germline, and the parental epigenetic memories can be maintained following fertilization and induce further allele-specific transcription and chromatin modifications of single or multiple neighboring genes, known as imprinted genes. To date, more than 260 imprinted genes have been identified in the mouse genome, most of which are controlled by imprinted germline differentially methylated regions (gDMRs) that exhibit parent-of-origin specific DNA methylation, which is considered primary imprint. Recent studies provide evidence that a subset of gDMR-less, placenta-specific imprinted genes is controlled by maternal-derived histone modifications. To further understand DNA methylation-dependent (canonical) and -independent (non-canonical) imprints, this review summarizes the loci under the control of each type of imprinting in the mouse and compares them with the respective homologs in other rodents. Understanding epigenetic systems that differ among loci or species may provide new models for exploring genetic regulation and evolutionary divergence.

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Section: Canonical and Non-canonical Imprinting In The Other Rodentsmentioning

confidence: 99%

Canonical and Non-canonical Genomic Imprinting in Rodents

Kobayashi

2021

Front. Cell Dev. Biol.

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“…A combination of factors appears to mediate maintenance in mice. Bartolomei 2014, Chang andBartolomei 2020). Temporal disruption occurring between the establishment and maintenance of epigenetic marks can lead to loss of methylation (Ginart et al 2016).…”

Section: Timing Of Ic2 Lommentioning

confidence: 99%

Epigenetic mosaicism and cell burden in Beckwith–Wiedemann syndrome due to loss of methylation at imprinting control region 2

Duffy

Hathaway

Klein

et al. 2021

Cold Spring Harb Mol Case Stud

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Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth disorder caused by epigenetic alterations on chromosome 11p15.5. Most molecular changes are sporadic and are thought to occur in a mosaic pattern. Thereby, the distribution of affected cells differs between tissues for each individual which can complicate genotype-phenotype correlations. In two of the BWS molecular subtypes, tissue mosaicism has been demonstrated; however, mosaicism has not been specifically studied in the most common cause of BWS, loss of methylation at KCNQ1OT1:TSS DMR (IC2 LOM). The increased prevalence of twinning associated with the IC2 LOM subtype and the discordant phenotypes between the twins previously led to the proposal of diffused epigenetic mosaicism leading to asymmetric distribution of affected cells during embryonic development. In this study, we evaluated the level of methylation detected in 64 samples collected from 30 patients affected by IC2 LOM. We demonstrate that the IC2 LOM defect can occur in mosaic and non-mosaic patterns, and tissues from the same patient can show variable patterns, which suggests this asymmetric distribution during development. We further suggest that the clinical phenotype in patients with BWS IC2 LOM is correlated with the epigenetic burden of affected cells in each tissue type. This series is the first report to demonstrate tissue mosaicism within the IC2 LOM epigenotype and consideration of this mosaicism is necessary to understanding the pathogenesis of BWS.

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“…The imprinted domain harboring the H19 and Insulin-like growth factor 2 ( Igf2 ) genes maps to the mouse distal chromosome 7 and is orthologous with the telomeric domain of the human chromosome 11p15.5 cluster ( 3 ). The Igf2 gene is expressed from the paternal allele and encodes a protein promoting fetal growth ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

“…Although the function of IC1 appears well conserved, its DNA sequence is very different in the human and mouse species. While the human IC1 (hIC1) contains seven CTCF target sites (CTSs) included in repetitive sequences overall spanning about 5 kb, the mouse IC1 (mIC1) is shorter (about 2 kb), non-repetitive and contains only four CTSs ( 3 ) ( Fig. 1A ).…”

Section: Introductionmentioning

confidence: 99%

The number of the CTCF binding sites of the H19/IGF2:IG-DMR correlates with DNA methylation and expression imprinting in a humanized mouse model

Freschi

Prete

Pignata

et al. 2021

Human Molecular Genetics

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The reciprocal parent of origin-specific expression of H19 and IGF2 is controlled by the H19/IGF2:IG-DMR (IC1), whose maternal allele is unmethylated and acts as a CTCF-dependent insulator. In humans, internal IC1 deletions are associated with Beckwith–Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS), depending on their parental origin. These genetic mutations result in aberrant DNA methylation, deregulation of IGF2/H19 and disease with incomplete penetrance. However, the mechanism linking the microdeletions to altered molecular and clinical phenotypes remains unclear. To address this issue, we have previously generated and characterized two knock-in mouse lines with the human wild-type (hIC1wt) or mutant (hIC1∆2.2) IC1 allele replacing the endogenous mouse IC1 (mIC1). Here, we report an additional knock-in line carrying a mutant hIC1 allele with an internal 1.8 kb deletion (hIC1∆1.8). The phenotype of these mice is different from that of the hIC1∆2.2-carrying mice, partially resembling hIC1wt animals. Indeed, proper H19 and Igf2 imprinting and normal growth phenotype were evident in the mice with maternal transmission of hIC1Δ1.8, while low DNA methylation and non-viable phenotype characterize its paternal transmission. In contrast to hIC1wt, E15.5 embryos that paternally inherit hIC1Δ1.8 displayed variegated hIC1 methylation. In addition, increased Igf2 expression, correlating with increased body weight, was found in one third of these mice. Chromatin immunoprecipitation experiments in mouse embryonic stem cells carrying the three different hIC1 alleles demonstrate that the number of CTCF target sites influences its binding to hIC1, indicating that in the mouse, CTCF binding is key to determining hIC1 methylation and Igf2 expression.

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

Cited by 35 publications

References 145 publications

Canonical and Non-canonical Genomic Imprinting in Rodents

Canonical and Non-canonical Genomic Imprinting in Rodents

Epigenetic mosaicism and cell burden in Beckwith–Wiedemann syndrome due to loss of methylation at imprinting control region 2

The number of the CTCF binding sites of the H19/IGF2:IG-DMR correlates with DNA methylation and expression imprinting in a humanized mouse model

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