Profound alterations of the chromatin architecture at chromosome 11p15.5 in cells from Beckwith-Wiedemann and Silver-Russell syndromes patients

Rovina, Davide; Vecchia, Marta La; Cortesi, Alice; Fontana, Laura; Pesant, Matthieu; Maitz, Silvia; Tabano, Silvia; Bodega, Beatrice; Miozzo, Monica; Sirchia, Silvia Maria

doi:10.1038/s41598-020-65082-1

Cited by 14 publications

(30 citation statements)

References 49 publications

(66 reference statements)

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“…The presence of MLID supports, indeed, the hypothesis of imprinting gene networks involved in the cross-talk among imprinted loci, probably mediated by complex chromatin structures and ncRNAs [ 39 , 40 ]. This hypothesis is also supported by recent evidence in BWS patients on the loss of the chromatin structure of the IGF2/H19 and CDKN1C/KCNQ1OT1 domains, which disrupts the fine-tuned control of gene expression in the two clusters [ 41 ]. The chromatin architecture of these domains differs between the maternal and paternal allele, and these allele-specific structures are required for the correct expression of the imprinted genes within these domains.…”

Section: Genetic and Epigenetic Alterations In Bwssupporting

confidence: 58%

“…In healthy cells, the IGF2/H19 and CDKN1C/KCNQ1OT1 domains fold in complex chromatin conformations that facilitate the control of imprinted loci mediated by distant enhancers. In BWS cells, the profound alterations of such chromatin architectures lead to the loss of the cross-talk between the two domains and the impairment of the correct expression of imprinted genes [ 41 ].…”

Section: Genetic and Epigenetic Alterations In Bwsmentioning

confidence: 99%

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Clinical and Molecular Diagnosis of Beckwith-Wiedemann Syndrome with Single- or Multi-Locus Imprinting Disturbance

Fontana

Tabano

Maitz

et al. 2021

IJMS

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Beckwith-Wiedemann syndrome (BWS) is a clinically and genetically heterogeneous overgrowth disease. BWS is caused by (epi)genetic defects at the 11p15 chromosomal region, which harbors two clusters of imprinted genes, IGF2/H19 and CDKN1C/KCNQ1OT1, regulated by differential methylation of imprinting control regions, H19/IGF2:IG DMR and KCNQ1OT1:TSS DMR, respectively. A subset of BWS patients show multi-locus imprinting disturbances (MLID), with methylation defects extended to other imprinted genes in addition to the disease-specific locus. Specific (epi)genotype-phenotype correlations have been defined in order to help clinicians in the classification of patients and referring them to a timely diagnosis and a tailored follow-up. However, specific phenotypic correlations have not been identified among MLID patients, thus causing a debate on the usefulness of multi-locus testing in clinical diagnosis. Finally, the high incidence of BWS monozygotic twins with discordant phenotypes, the high frequency of BWS among babies conceived by assisted reproductive technologies, and the female prevalence among BWS-MLID cases provide new insights into the timing of imprint establishment during embryo development. In this review, we provide an overview on the clinical and molecular diagnosis of single- and multi-locus BWS in pre- and post-natal settings, and a comprehensive analysis of the literature in order to define possible (epi)genotype-phenotype correlations in MLID patients.

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Section: Genetic and Epigenetic Alterations In Bwssupporting

confidence: 58%

Section: Genetic and Epigenetic Alterations In Bwsmentioning

confidence: 99%

Clinical and Molecular Diagnosis of Beckwith-Wiedemann Syndrome with Single- or Multi-Locus Imprinting Disturbance

Fontana

Tabano

Maitz

et al. 2021

IJMS

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“…Here, CTCF binds the unmethylated paternal copy of the ICR, which also comprises the promoter that drives Kcnq1ot1 expression on this parental chromosome [ 105 ]. The allelic CTCF binding mediates specific long-range interactions on the paternal chromosome, detected by 3C-based technology, that correlate with the allelic expression of several genes within the domain [ 75 , 102 , 106 ]. Another locus that shows both allelic CTCF binding and allelic lncRNA expression is the imprinted Zdbf2 domain [ 107 ].…”

Section: Emerging Roles Of Imprinted Lncrnas In Chromatin Architecturementioning

confidence: 99%

Exploring chromatin structural roles of non-coding RNAs at imprinted domains

Llères

Imaizumi

Feil

2021

Biochemical Society Transactions

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Different classes of non-coding RNA (ncRNA) influence the organization of chromatin. Imprinted gene domains constitute a paradigm for exploring functional long ncRNAs (lncRNAs). Almost all express an lncRNA in a parent-of-origin dependent manner. The mono-allelic expression of these lncRNAs represses close by and distant protein-coding genes, through diverse mechanisms. Some control genes on other chromosomes as well. Interestingly, several imprinted chromosomal domains show a developmentally regulated, chromatin-based mechanism of imprinting with apparent similarities to X-chromosome inactivation. At these domains, the mono-allelic lncRNAs show a relatively stable, focal accumulation in cis. This facilitates the recruitment of Polycomb repressive complexes, lysine methyltranferases and other nuclear proteins — in part through direct RNA–protein interactions. Recent chromosome conformation capture and microscopy studies indicate that the focal aggregation of lncRNA and interacting proteins could play an architectural role as well, and correlates with close positioning of target genes. Higher-order chromatin structure is strongly influenced by CTCF/cohesin complexes, whose allelic association patterns and actions may be influenced by lncRNAs as well. Here, we review the gene-repressive roles of imprinted non-coding RNAs, particularly of lncRNAs, and discuss emerging links with chromatin architecture.

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“…Recently, Rovina et al. ( 50 ) reported an interaction between IC1 and IC2 in a limited number of patient lymphoblastoid cell lines. To determine whether we observed such an interaction in our patient fibroblast lines, we expanded the window of interactions.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, a study by Rovina et al. demonstrated that interaction between the DMR and the KCNQ1 intron 2 CTCF sites is significantly reduced in BWS patient cell lines ( 50 ). Together, these results suggest that CTCF performs an important function in organizing the imprinted locus and may precede initial deposition of DNA methylation or play a role in maintaining DNA methylation.…”

Section: Introductionmentioning

confidence: 99%

The role of CTCF in the organization of the centromeric 11p15 imprinted domain interactome

Naveh

Deegan

Huhn

et al. 2021

Nucleic Acids Research

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DNA methylation, chromatin-binding proteins, and DNA looping are common components regulating genomic imprinting which leads to parent-specific monoallelic gene expression. Loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15 is the most common cause of the imprinting overgrowth disorder Beckwith-Wiedemann Syndrome (BWS). Here, we report a familial transmission of a 7.6 kB deletion that ablates the core promoter of KCNQ1. This structural alteration leads to IC2 LOM and causes recurrent BWS. We find that occupancy of the chromatin organizer CTCF is disrupted proximal to the deletion, which causes chromatin architecture changes both in cis and in trans. We also profile the chromatin architecture of IC2 in patients with sporadic BWS caused by isolated LOM to identify conserved features of IC2 regulatory disruption. A strong interaction between CTCF sites around KCNQ1 and CDKN1C likely drive their expression on the maternal allele, while a weaker interaction involving the imprinting control region element may impede this connection and mediate gene silencing on the paternal allele. We present an imprinting model in which KCNQ1 transcription is necessary for appropriate CTCF binding and a novel chromatin conformation to drive allele-specific gene expression.

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Profound alterations of the chromatin architecture at chromosome 11p15.5 in cells from Beckwith-Wiedemann and Silver-Russell syndromes patients

Cited by 14 publications

References 49 publications

Clinical and Molecular Diagnosis of Beckwith-Wiedemann Syndrome with Single- or Multi-Locus Imprinting Disturbance

Clinical and Molecular Diagnosis of Beckwith-Wiedemann Syndrome with Single- or Multi-Locus Imprinting Disturbance

Exploring chromatin structural roles of non-coding RNAs at imprinted domains

The role of CTCF in the organization of the centromeric 11p15 imprinted domain interactome

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