Oct motif variants in Beckwith–Wiedemann syndrome patients disrupt maintenance of the hypomethylated state of the <i>H19/IGF2</i> imprinting control region

Kubo, Shunsuke; Murata, Chihiro; Okamura, Hanayo; Sakasegawa, Taku; Sakurai, Chiye; Hatsuzawa, Kiyotaka; Hori, Naohiro

doi:10.1002/1873-3468.13750

Cited by 6 publications

(5 citation statements)

References 35 publications

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“…Thus, the evidence suggests that one way in which TFs protect from methylation may by the placement of H3K4me3 and the recruitment of a range of co-factors that promote a hypomethylated state on DNA. Importantly, there is solid evidence that TFs play a causal role in protecting from de novo DNA methylation [41,63], suggesting multiple, possibly redundant, modes of hypomethylation maintenance. Taken together, our results demonstrate that TFs are capable of maintaining a hypomethylated state of CpGs near their binding sites trans-generationally.…”

Section: Discussionmentioning

confidence: 99%

Protection from DNA re-methylation by transcription factors in primordial germ cells and pre-implantation embryos can explain trans-generational epigenetic inheritance

Kremsky

Corcés

2020

Genome Biol

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Background: A growing body of evidence suggests that certain epiphenotypes can be passed across generations via both the male and female germlines of mammals. These observations have been difficult to explain owing to a global loss of the majority of known epigenetic marks present in parental chromosomes during primordial germ cell development and after fertilization. Results: By integrating previously published BS-seq, DNase-seq, ATAC-seq, and RNAseq data collected during multiple stages of primordial germ cell and preimplantation development, we find that the methylation status of the majority of CpGs genome-wide is restored after global de-methylation, despite the fact that global CpG methylation drops to 10% in primordial germ cells and 20% in the inner cell mass of the blastocyst. We estimate the proportion of such CpGs with preserved methylation status to be 78%. Further, we find that CpGs at sites bound by transcription factors during the global re-methylation phases of germline and embryonic development remain hypomethylated across all developmental stages observed. On the other hand, CpGs at sites not bound by transcription factors during the global re-methylation phase have high methylation levels prior to global demethylation, become de-methylated during global de-methylation, and then become re-methylated. Conclusions: The results suggest that transcription factors can act as carriers of epigenetic information during germ cell and pre-implantation development by ensuring that the methylation status of CpGs is maintained. These findings provide the basis for a mechanistic description of trans-generational inheritance of epigenetic information in mammals.

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Section: Discussionmentioning

confidence: 99%

Protection from DNA re-methylation by transcription factors in primordial germ cells and pre-implantation embryos can explain trans-generational epigenetic inheritance

Kremsky

Corcés

2020

Genome Biol

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“…Continued promoter activity at Meg3 protects indeed against the acquisition of de novo DNA methylation in early embryonic cells [108,109]. Point mutations within transcription-factor binding sites at the ICRs of the human IGF2-H19 and KCNQ1 domains have provided evidence for such a scenario as well [110][111][112][113][114]. Conversely, CTCF itself may protect the unmethylated allele against de novo DNA methylation [110,111,115,116], thus ensuring continued transcription of the lncRNA from the unmethylated parental allele only.…”

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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“…Three Oct motifs variants found in BWS patients disrupt hD1-dependent DNA demethylation and cause the stack of methylation ( Kubo et al, 2020 ). Single nucleotide substitutions in hD1 Oct motifs present in BWS patients show hypermethylation in H19/IGF2 :IG-DMR coupled with histone modifications: maternal aberrant DNA methylation is connected with reduction of H3K4me2 and H3K9ac and increase of H3K9me3 and H3K27me3 ( Kubo et al, 2020 ). KCNQ1OT1 :TSS-DMR contains six different imprinted genes: KCNQ1 , KCNQ1OT1 , CDKN1C , SLC22A18 , TSSC3 , and PHLDA2 .…”

Section: Role Of Epigenetic Alterations In Bwsmentioning

confidence: 99%

“…Interestingly in BWS patients, SO motifs are mutated or deleted. Three Oct motifs variants found in BWS patients disrupt hD1-dependent DNA demethylation and cause the stack of methylation (Kubo et al, 2020). Single nucleotide substitutions in hD1 Oct motifs present in BWS FIGURE 1 | On the maternal allele: CTCF binding H19/IGF2:IG-DMR, prevents IGF2 from accessing the shared enhancers located on the H19 side.…”

Section: Role Of Epigenetic Alterations In Bwsmentioning

confidence: 99%

“…patients show hypermethylation in H19/IGF2:IG-DMR coupled with histone modifications: maternal aberrant DNA methylation is connected with reduction of H3K4me2 and H3K9ac and increase of H3K9me3 and H3K27me3 (Kubo et al, 2020). KCNQ1OT1:TSS-DMR contains six different imprinted genes: KCNQ1, KCNQ1OT1, CDKN1C, SLC22A18, TSSC3, and PHLDA2.…”

Section: Role Of Epigenetic Alterations In Bwsmentioning

confidence: 99%

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Preclinical and Clinical Epigenetic-Based Reconsideration of Beckwith-Wiedemann Syndrome

et al. 2020

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Epigenetics has achieved a profound impact in the biomedical field, providing new experimental opportunities and innovative therapeutic strategies to face a plethora of diseases. In the rare diseases scenario , Beckwith-Wiedemann syndrome (BWS) is a pediatric pathological condition characterized by a complex molecular basis, showing alterations in the expression of different growth-regulating genes. The molecular origin of BWS is associated with impairments in the genomic imprinting of two domains at the 11p15.5 chromosomal region. The first domain contains three different regions: insulin growth like factor gene ( IGF2 ), H19 , and abnormally methylated DMR1 region. The second domain consists of cell proliferation and regulating-genes such as CDKN1C gene encoding for cyclin kinase inhibitor its role is to block cell proliferation. Although most cases are sporadic, about 5–10% of BWS patients have inheritance characteristics. In the 11p15.5 region, some of the patients have maternal chromosomal rearrangements while others have Uniparental Paternal Disomy UPD(11)pat. Defects in DNA methylation cause alteration of genes and the genomic structure equilibrium leading uncontrolled cell proliferation, which is a typical tumorigenesis event. Indeed, in BWS patients an increased childhood tumor predisposition is observed. Here, we summarize the latest knowledge on BWS and focus on the impact of epigenetic alterations to an increased cancer risk development and to metabolic disorders. Moreover, we highlight the correlation between assisted reproductive technologies and this rare disease. We also discuss intriguing aspects of BWS in twinning. Epigenetic therapies in clinical trials have already demonstrated effectiveness in oncological and non-oncological diseases. In this review, we propose a potential “epigenetic-based” approaches may unveil new therapeutic options for BWS patients. Although the complexity of the syndrome is high, patients can be able to lead a normal life but tumor predispositions might impair life expectancy. In this sense epigenetic therapies should have a supporting role in order to guarantee a good prognosis.

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Oct motif variants in Beckwith–Wiedemann syndrome patients disrupt maintenance of the hypomethylated state of the H19/IGF2 imprinting control region

Cited by 6 publications

References 35 publications

Protection from DNA re-methylation by transcription factors in primordial germ cells and pre-implantation embryos can explain trans-generational epigenetic inheritance

Protection from DNA re-methylation by transcription factors in primordial germ cells and pre-implantation embryos can explain trans-generational epigenetic inheritance

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

Preclinical and Clinical Epigenetic-Based Reconsideration of Beckwith-Wiedemann Syndrome

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