Deletion of the Williams Beuren syndrome critical region unmasks facioscapulohumeral muscular dystrophy

Rodolico, Carmelo; Politano, Luisa; Portaro, Simona; Murru, S; Boccone, Loredana; Sera, Francesco; Passamano, Luigia; Brizzi, Teresa; Tupler, Rossella

doi:10.1016/j.ejpn.2020.05.006

Cited by 4 publications

(4 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the heterozygous state, a D4Z4 reduction might produce a subclinical sensitized condition that requires other epigenetic mechanisms or a contributing factor to cause overt myopathy. In some cases, it might be by the simultaneous heterozygosity for a different and recessive myopathy, as suggested by many reports in which the FSHD contractions are found in association with a second molecular defect [75,[93][94][95][96][97][98][99][100][101][102]. Alternatively, as our findings are suggesting, environmental changes that affect chromatin modifications at 4q35 could generate an abnormal quantity of subtelomeric transcripts in cells with a DRA.…”

Section: Novel Modes Of Regulation Of Telomeric 4q35 Transcripts Prov...mentioning

confidence: 53%

Post-transcriptional RNA stabilization of telomere-proximal RNAs FRG2, DBET, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length

Salsi,

Losi,

Salani

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Reduced copy number of the D4Z4 macrosatellite at human chromosome 4q35 is associated with facioscapulohumeral muscular dystrophy (FSHD). A pervasive idea is that chromatin alterations at the 4q35 locus following D4Z4 repeat unit deletion lead to disease via inappropriate expression of nearby genes. Here, we sought to analyze transcription and chromatin characteristics across 4q35 and how these are affected by D4Z4 deletions and exogenous stresses. Results: We found that the 4q subtelomere is subdivided into discrete domains, each with characteristic chromatin features associated with distinct gene expression profiles. Centromere-proximal genes within 4q35 (ANT1, FAT1 and FRG1) display active histone marks at their promoters. In contrast, poised or repressed markings are present at telomere-proximal loci including FRG2, DBE-T and D4Z4. We discovered that these discrete domains undergo region-specific chromatin changes upon treatment with chromatin enzyme inhibitors or genotoxic drugs. We demonstrated that the 4q35 telomere-proximal FRG2, DBE-T and D4Z4-derived transcripts are induced upon DNA damage to levels inversely correlated with the D4Z4 repeat number, are stabilized through post-transcriptional mechanisms upon DNA damage, and are bound to chromatin. Conclusion: Our study reveals unforeseen biochemical features of RNAs from clustered transcription units within the 4q35 subtelomere. Specifically, the FRG2, DBE-T and D4Z4-derived transcripts are chromatin-associated and are stabilized post-transcriptionally after induction by genotoxic stress. Remarkably, the extent of this response is modulated by the copy number of the D4Z4 repeats, raising new hypotheses about their regulation and function in human biology and disease.

show abstract

Section: Novel Modes Of Regulation Of Telomeric 4q35 Transcripts Prov...mentioning

confidence: 53%

Post-transcriptional RNA stabilization of telomere-proximal RNAs FRG2, DBET, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length

Salsi,

Losi,

Salani

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the heterozygous state, a D4Z4 reduction might produce a subclinical sensitized condition that requires other epigenetic mechanisms or a contributing factor to cause overt myopathy. In some cases, it might be by the simultaneous heterozygosity for a different and recessive myopathy, as suggested by many reports in which the FSHD contractions are found in association with a second molecular defect [75,[93][94][95][96][97][98][99][100][101][102]. Alternatively, as our ndings are suggesting, environmental changes that affect chromatin modi cations at 4q35 could generate an abnormal quantity of subtelomeric transcripts in cells with a DRA.…”

Section: Figure 5 4q35 Genes Regulation Upon Different Stimuli Re Ect...mentioning

confidence: 64%

Post-transcriptional RNA stabilization of telomere-proximal RNAs FRG2, DBET, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length

Salsi,

Losi,

Salani

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Background Reduced copy number of the D4Z4 macrosatellite at human chromosome 4q35 is associated with facioscapulohumeral muscular dystrophy (FSHD). A pervasive idea is that chromatin alterations at the 4q35 locus following D4Z4 repeat unit deletion lead to disease via inappropriate expression of nearby genes. Here, we sought to analyze transcription and chromatin characteristics across 4q35 and how these are affected by D4Z4 deletions and exogenous stresses. Results We found that the 4q subtelomere is subdivided into discrete domains, each with characteristic chromatin features associated with distinct gene expression profiles. Centromere-proximal genes within 4q35 (ANT1, FAT1 and FRG1) display active histone marks at their promoters. In contrast, poised or repressed markings are present at telomere-proximal loci including FRG2, DBE-T and D4Z4. We discovered that these discrete domains undergo region-specific chromatin changes upon treatment with chromatin enzyme inhibitors or genotoxic drugs. We demonstrated that the 4q35 telomere-proximal FRG2, DBE-T and D4Z4-derived transcripts are induced upon DNA damage to levels inversely correlated with the D4Z4 repeat number, are stabilized through post-transcriptional mechanisms upon DNA damage, and are bound to chromatin. Conclusion Our study reveals unforeseen biochemical features of RNAs from clustered transcription units within the 4q35 subtelomere. Specifically, the FRG2, DBE-T and D4Z4-derived transcripts are chromatin-associated and are stabilized post-transcriptionally after induction by genotoxic stress. Remarkably, the extent of this response is modulated by the copy number of the D4Z4 repeats, raising new hypotheses about their regulation and function in human biology and disease.

show abstract

“…As shown in Table 1, the platform has been successfully applied to many different aspects of FSHD research: 1) the CCEF validation [16] 2) the genotype/phenotype characterization of people carrying specific molecular features: 1-3 DRA [14] or 7-8 DRA [21] or 9-10 [22] 3) follow up studies [23]. The MOMIS FSHD Web Platform has also been used 4) for molecular research on D4Z4 epigenetic regulation [24] or 5) to identify genetic interactions with other rare diseases [25].…”

Section: The Momis Fshd Web Platform Application In Clinical Researchmentioning

confidence: 99%

The Italian National Registry for FSHD: an enhanced data integration and an analytics framework towards Smart Health Care and Precision Medicine for a rare disease

Bettio

Salsi

Orsini³

et al. 2021

Orphanet J Rare Dis

Self Cite

View full text Add to dashboard Cite

Background The Italian Clinical network for FSHD (ICNF) has established the Italian National Registry for FSHD (INRF), collecting data from patients affected by Facioscapulohumeral dystrophy (FSHD) and their relatives. The INRF has gathered data from molecular analysis, clinical evaluation, anamnestic information, and family history from more than 3500 participants. Methods A data management framework, called Mediator Environment for Multiple Information Sources (MOMIS) FSHD Web Platform, has been developed to provide charts, maps and search tools customized for specific needs. Patients’ samples and their clinical information derives from the Italian Clinical network for FSHD (ICNF), a consortium consisting of fourteen neuromuscular clinics distributed across Italy. The tools used to collect, integrate, and visualize clinical, molecular and natural history information about patients affected by FSHD and their relatives are described. Results The INRF collected the molecular data regarding FSHD diagnosis conducted on 7197 subjects and identified 3362 individuals carrying a D4Z4 Reduced Allele (DRA): 1634 were unrelated index cases. In 1032 cases the molecular testing has been extended to 3747 relatives, 1728 carrying a DRA. Since 2009 molecular analysis has been accompanied by clinical evaluation based standardized evaluation protocols. In the period 2009–2020, 3577 clinical forms have been collected, 2059 follow the Comprehensive Clinical Evaluation form (CCEF). The integration of standardized clinical information and molecular data has made possible to demonstrate the wide phenotypic variability of FSHD. The MOMIS (Mediator Environment for Multiple Information Sources) data integration framework allowed performing genotype–phenotype correlation studies, and generated information of medical importance either for clinical practice or genetic counseling. Conclusion The platform implemented for the FSHD Registry data collection based on OpenClinica meets the requirement to integrate patient/disease information, as well as the need to adapt dynamically to security and privacy concerns. Our results indicate that the quality of data collection in a multi-integrated approach is fundamental for clinical and epidemiological research in a rare disease and may have great value in allowing us to redefine diagnostic criteria and disease markers for FSHD. By extending the use of the MOMIS data integration framework to other countries and the longitudinal systematic collection of standardized clinical data will facilitate the understanding of disease natural history and offer valuable inputs towards trial readiness. This approach is of high significance to FSHD medical community and also to rare disease research in general.

show abstract

Deletion of the Williams Beuren syndrome critical region unmasks facioscapulohumeral muscular dystrophy

Cited by 4 publications

References 20 publications

Post-transcriptional RNA stabilization of telomere-proximal RNAs FRG2, DBET, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length

Post-transcriptional RNA stabilization of telomere-proximal RNAs FRG2, DBET, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length

Post-transcriptional RNA stabilization of telomere-proximal RNAs FRG2, DBET, D4Z4 at human 4q35 in response to genotoxic stress and D4Z4 macrosatellite repeat length

The Italian National Registry for FSHD: an enhanced data integration and an analytics framework towards Smart Health Care and Precision Medicine for a rare disease

Contact Info

Product

Resources

About