Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model

Greef, Jessica C. de; Krom, Yvonne D.; Hamer, Bianca den; Snider, Lauren; Hiramuki, Yosuke; Akker, Rob F. P. van den; Breslin, Kelsey; Pakusch, Miha; Salvatori, Daniela; Slütter, Bram; Tawil, Rabi; Blewitt, Marnie E.; Tapscott, Stephen J.; Maarel, Silvère M. van der

doi:10.1093/hmg/ddx437

Cited by 25 publications

(47 citation statements)

References 43 publications

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“…SMCHD1 mutations do not only seem to play a critical role in FSHD2, but also have been identified as a disease modifier in FSHD1: Patients with both an FSHD1 allele and an SMCHD1 mutation were more severely affected than affected family members with only 1 of the 2 genetic mutations [20,21]. The modifier role of SMCHD1 on disease severity has also been studied in a mouse model by crossbreeding D4Z4-2.5 mice with mice haploinsufficient for SMCHD1 which resulted in an exacerbated phenotype [22]. It will be important to learn more about how SMCHD1 variants affect the D4Z4 structure and how this influences FSHD disease variability and penetrance.…”

Section: The Concept Of Epigenetic Susceptibilitymentioning

confidence: 99%

“…Expression of DUX4 has been reported in thymus and keratinocytes [27], suggesting that DUX4 may have a function outside the germline [22]. Hence, future research will need to clarify whether therapeutic repression of DUX4 might have detrimental side effects and whether treatments will need to be tissue selective.…”

Section: Molecular Pathomechanism: Dux4 Toxicitymentioning

confidence: 99%

“…A mouse model which integrates a pathogenic FSHD1 D4Z4 repeat size of 2.5 repeats including the distal polyadenylation site shows low levels of DUX4 mRNA and protein in skeletal muscle but lacks a muscle phenotype. One possible hypothesis for the failure of modeling the FSHD muscle phenotype was the complex spatial and temporal expression patterns of the transgene [22]. Nevertheless, since this model carries the D4Z4 repeats, it can still be used to study the epigenetic regulation of the D4Z4 repeat array involving modifiers that bind to D4Z4, such as SMCHD1.…”

Section: Animal Modelsmentioning

confidence: 99%

“…Nevertheless, since this model carries the D4Z4 repeats, it can still be used to study the epigenetic regulation of the D4Z4 repeat array involving modifiers that bind to D4Z4, such as SMCHD1. When levels of SMCHD1 are decreased, DUX4 mRNA is more abundant with a more severe skin phenotype, albeit without showing symptoms or signs involving the muscle [22].…”

Section: Animal Modelsmentioning

confidence: 99%

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Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Hamel

Tawil

2018

Neurotherapeutics

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A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of DUX4, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. DUX4 derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in SMCHD1, a gene involved in chromatin methylation (FSHD2). The resulting expression of DUX4, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting DUX4 expression or blocking 1 or more of several downstream effects of DUX4. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed.

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Section: The Concept Of Epigenetic Susceptibilitymentioning

confidence: 99%

Section: Molecular Pathomechanism: Dux4 Toxicitymentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

Section: Animal Modelsmentioning

confidence: 99%

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Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Hamel

Tawil

2018

Neurotherapeutics

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“…The MMTV-Cre transgene line A (48) was backcrossed for more than 10 generations onto the C57BL/6 background from the FVB/N background for use in this study. This was used in combination with a Smchd1 deleted allele (Smchd1 -) in trans to the Smchd1 floxed (Smchd1 fl ) allele (49). The Smchd1allele was generated from the Smchd1 fl allele using a line of C57BL/6 mice expressing a constitutive Cre transgene (50).…”

Section: Methodsmentioning

confidence: 99%

Smchd1is a maternal effect gene required for autosomal imprinting

Wanigasuriya

Gouil

Kinkel

et al. 2020

Preprint

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Genomic imprinting establishes parental allelebiased expression of a suite of mammalian genes based on parent-of-origin specific epigenetic marks. These marks are under the control of maternal effect proteins supplied in the oocyte. Here we report the epigenetic repressor Smchd1 as a novel maternal effect gene that regulates imprinted expression of 16 genes. Most Smchd1-sensitive genes only show loss of imprinting post-implantation, indicating maternal Smchd1's long-lived epigenetic effect. Sm-chd1-sensitive genes include both those controlled by germline polycomb marks and germline DNA methylation imprints; however, Smchd1 differs to other maternal effect genes that regulate the latter group, as Smchd1 does not affect germline DNA methylation imprints. Instead, Smchd1-sensitive genes are united by their reliance on polycomb-mediated histone methylation marks as germline or secondary imprints. We propose that Smchd1 translates these imprints to establish a heritable chromatin state required for imprinted expression later in development, revealing a new mechanism for maternal effect genes. Smchd1 | maternal effect gene | genomic imprinting | germline methylation imprints | allele-specific expression | imprinted H3K27me3

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Preimplantation embryo gene expression: 56 years of discovery, and counting

Latham

2023

Molecular Reproduction Devel

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The biology of preimplantation embryo gene expression began 56 years ago with studies of the effects of protein synthesis inhibition and discovery of changes in embryo metabolism and related enzyme activities. The field accelerated rapidly with the emergence of embryo culture systems and progressively evolving methodologies that have allowed early questions to be re-addressed in new ways and in greater detail, leading to deeper understanding and progressively more targeted studies to discover ever more fine details. The advent of technologies for assisted reproduction, preimplantation genetic testing, stem cell manipulations, artificial gametes, and genetic manipulation, particularly in experimental animal models and livestock species, has further elevated the desire to understand preimplantation development in greater detail. The questions that drove enquiry from the earliest years of the field remain drivers of enquiry today. Our understanding of the crucial roles of oocyteexpressed RNA and proteins in early embryos, temporal patterns of embryonic gene expression, and mechanisms controlling embryonic gene expression has increased exponentially over the past five and a half decades as new analytical methods emerged. This review combines early and recent discoveries on gene regulation and expression in mature oocytes and preimplantation stage embryos to provide a comprehensive understanding of preimplantation embryo biology and to anticipate exciting future advances that will build upon and extend what has been discovered so far.

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Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model

Cited by 25 publications

References 43 publications

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Smchd1is a maternal effect gene required for autosomal imprinting

Preimplantation embryo gene expression: 56 years of discovery, and counting

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