Correlation analysis of clinical parameters with epigenetic modifications in the <i>DUX4</i> promoter in FSHD

Balog, Judit; Thijssen, Peter; Greef, Jessica C. de; Shah, Bharati; Engelen, B.G.M. van; Yokomori, Kyoko; Tapscott, Stephen J.; Tawil, Rabi; Maarel, Silvère M. van der

doi:10.4161/epi.20001

Cited by 50 publications

(53 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experimental hurdles in FSHD research. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars observed between FSHD and healthy genomes, there are also marked changes in histone PTMs and associated proteins (6,26,95,180); however, due to challenges in analyzing the FSHD-associated array (Box 1), the story is still incomplete.…”

Section: D4z4 Chromatinmentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression. Recent Advances: In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD. Critical Issues: Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets? Future Directions: Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies.

show abstract

Section: D4z4 Chromatinmentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…56 Interestingly, FSHD2 patients display loss of heterochromatin not only from 4q35 but also from 10q26, where a macrosatellite repeat array almost identical to D4Z4 exists, suggesting a functional communication between these chromosomes, reminiscent of transvection in Drosophila. 57 Consistent with this, somatic pairing of 4q35 and 10q26 D4Z4 has been reported.…”

Section: Open Questionsmentioning

confidence: 99%

“…Recently, a possible relationship between clinical and epigenetic parameters was reported. 56 It would be important to determine if DBE-T plays a role in mediating the epigenetic component of the clinical severity in FSHD.…”

Section: Open Questionsmentioning

confidence: 99%

A novel molecular mechanism in human genetic disease

2012

View full text Add to dashboard Cite

“…4 Both forms are associated with partial chromatin relaxation of the D4Z4 macrosatellite repeat array on the subtelomere of the long arm of chromosome 4 and transcriptional derepression of the D4Z4 unit-encoded DUX4 retrogene in skeletal muscle. [5][6][7][8][9] DUX4 is a germ line transcription factor that is normally repressed in somatic cells. 7 Its expression in skeletal muscle activates genes involved in germ line and early stem cell development, as well as specific classes of repeat elements, and overexpression of DUX4 in somatic cells causes cell death.…”

Section: Introductionmentioning

confidence: 99%

“…5 In FSHD1, chromatin relaxation and CpG hypomethylation are restricted to the contracted allele, whereas in FSHD2 chromatin relaxation and CpG hypomethylation occur at the D4Z4 repeat arrays of both copies of chromosome 4 and in the highly homologous repeat arrays on chromosome 10. 4,9 Heterozygous variants in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene on chromosome 18 account for the majority of FSHD2 cases. 14 SMCHD1 is an atypical member of the SMC gene superfamily, a family of proteins which is involved in chromosome condensation and cohesion, genome maintenance and gene regulation.…”

Section: Introductionmentioning

confidence: 99%

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

et al. 2015

Self Cite

View full text Add to dashboard Cite

Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 functionaffecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance.

show abstract

Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD

Abstract: Silvère M. van der Maarel (2012) Correlation analysis of clinical parameters with epigenetic modifications in the DUX4 promoter in FSHD, Epigenetics, 7:6, 579-584,

Cited by 50 publications

References 14 publications

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

A novel molecular mechanism in human genetic disease

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

Contact Info

Product

Resources

About