Dataset Information

SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.

ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic derepression of the 4q-linked D4Z4 macrosatellite repeat resulting in inappropriate expression of the D4Z4 repeat-encoded DUX4 gene in skeletal muscle. In 5% of FSHD cases, D4Z4 chromatin relaxation is due to germline mutations in one of the chromatin modifiers SMCHD1, DNMT3B or LRIF1. The mechanism of SMCHD1- and LRIF1-mediated D4Z4 repression is not clear. We show that somatic loss-of-function of either SMCHD1 or LRIF1 does not result in D4Z4 chromatin changes and that SMCHD1 and LRIF1 form an auxiliary layer of D4Z4 repressive mechanisms. We uncover that SMCHD1, together with the long isoform of LRIF1, binds to the LRIF1 promoter and silences LRIF1 expression. The interdependency of SMCHD1 and LRIF1 binding differs between D4Z4 and the LRIF1 promoter, and both loci show different transcriptional responses to either early developmentally or somatically perturbed chromatin function of SMCHD1 and LRIF1.

SUBMITTER: Sikrova D

PROVIDER: S-EPMC10307901 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.

Šikrová Darina D Testa Alessandra M AM Willemsen Iris I van den Heuvel Anita A Tapscott Stephen J SJ Daxinger Lucia L Balog Judit J van der Maarel Silvère M SM

Communications biology 20230628 1

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic derepression of the 4q-linked D4Z4 macrosatellite repeat resulting in inappropriate expression of the D4Z4 repeat-encoded DUX4 gene in skeletal muscle. In 5% of FSHD cases, D4Z4 chromatin relaxation is due to germline mutations in one of the chromatin modifiers SMCHD1, DNMT3B or LRIF1. The mechanism of SMCHD1- and LRIF1-mediated D4Z4 repression is not clear. We show that somatic loss-of-function of either SMCHD1 or LRIF1 d ...[more]

PMID: 37380887

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Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disorder which is typically transmitted by an autosomal dominant pattern, although reduced penetrance and sporadic cases caused by de novo mutations, are often observed. FSHD may be caused by a contraction of a repetitive element, located on chromosome 4 (4q35). This locus is named D4Z4 and consists of 11 to more than 100 repeated units (RU). The D4Z4 is normally hypermethylated and the genes located on this locus are silenced. In case of FSHD, the D4Z4 region is characterized by 1-10 repeats and results in the region being hypomethylated. However, 5% of FSHD cases do not carry the short allele of D4Z4 region. To date, two forms of FSHD (FSHD1 and FSHD2) are known. FSHD2 is usually observed in patients without the D4Z4 fragment contraction and carrying variants in SMCHD1 (18p11.32) gene. We report the case of a young adult patient who shows severe symptoms of FSHD. Preliminary genetic analysis did not clarify the phenotype, therefore we decided to study the family members by genetic and epigenetic approaches. The analysis of D4Z4 fragment resulted to be 8 RU in the affected proband and in his father; 26 RU in the mother and 25 RU in the maternal uncle. SMCHD1 analysis revealed a heterozygous variation within the exon 41. The variant was detected in the proband, her mother and the uncle. Furthermore, epigenetic analysis of CpG6 methylation regions showed significant hypomethylation in the affected patient (54%) and in the mother (56%), in contrast to the father (88%) and the uncle (81%) carrying higher methylation levels. The analysis of DR1 methylation levels reported hypomethylation for the proband (19%), the mother (11%), and the uncle (16%). The father showed normal DR1 methylation levels (>30%). Given these results, the combined inheritance of SMCHD1 variant and the short fragment might explain the severe FSHD phenotype displayed by the proband. On this subject, SMCHD1 analysis should be promoted in a larger number of patients, even in presence of D4Z4 contractions, to facilitate the genotype-phenotype correlation as well as, to enable a more precise diagnosis and prognosis of the disease.

Dataset Information

SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.

Publications

SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action.

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