AI Article Synopsis
- Facioscapulohumeral dystrophy (FSHD) is caused by the contraction of D4Z4 repeats on chromosome 4q, affecting gene regulation due to mutations that serve as disease modifiers.
- The condition is characterized by disruption of heterochromatin and abnormal expression of the DUX4 transcription factor, but understanding this process has been complicated by genetic variability in patient muscle cells.
- This study developed isogenic cell lines to show how mutations influence D4Z4 heterochromatin differently, stabilizing DUX4 activation and revealing how it contributes to FSHD through downstream targets.
Article Abstract
Facioscapulohumeral dystrophy (FSHD) is linked to contraction of D4Z4 repeats on chromosome 4q with mutations acting as a disease modifier. D4Z4 heterochromatin disruption and abnormal upregulation of the transcription factor DUX4, encoded in the repeat, are the hallmarks of FSHD. However, defining the precise effect of D4Z4 contraction has been difficult because D4Z4 repeats are primate-specific and DUX4 expression is very rare in highly heterogeneous patient myocytes. We generated isogenic mutant cell lines harboring D4Z4 and/or mutations in a healthy human skeletal myoblast line. We found that the mutations affect D4Z4 heterochromatin differently, and that mutation or disruption of DNA methylation stabilizes otherwise variegated DUX4 target activation in D4Z4 contraction mutant cells, demonstrating the critical role of modifiers. Our study revealed amplification of the DUX4 signal through downstream targets, H3.X/Y and LEUTX. Our results provide important insights into how rare DUX4 expression leads to FSHD pathogenesis.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10951985 | PMC |
| http://dx.doi.org/10.1016/j.isci.2024.109357 | DOI Listing |
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Germline mutations in SMCHD1, DNMT3B and LRIF1 can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2). FSHD is an epigenetic skeletal muscle disorder in which partial failure in heterochromatinization of the D4Z4 macrosatellite repeat causes spurious expression of the repeat-embedded gene in skeletal muscle, ultimately leading to muscle weakness and wasting. All three proteins play a role in chromatin organization and gene silencing; however, their functional relationship has not been fully elucidated.
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Article Synopsis
- Facioscapulohumeral dystrophy (FSHD) is caused by the contraction of D4Z4 repeats on chromosome 4q, affecting gene regulation due to mutations that serve as disease modifiers.
- The condition is characterized by disruption of heterochromatin and abnormal expression of the DUX4 transcription factor, but understanding this process has been complicated by genetic variability in patient muscle cells.
- This study developed isogenic cell lines to show how mutations influence D4Z4 heterochromatin differently, stabilizing DUX4 activation and revealing how it contributes to FSHD through downstream targets.
CRISPR mediated targeting of DUX4 distal regulatory element represses DUX4 target genes dysregulated in Facioscapulohumeral muscular dystrophy.
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Facioscapulohumeral muscular dystrophy (FSHD) is a debilitating muscle disease that currently does not have an effective cure or therapy. The abnormal reactivation of DUX4, an embryonic gene that is epigenetically silenced in somatic tissues, is causal to FSHD. Disease-specific reactivation of DUX4 has two common characteristics, the presence of a non-canonical polyadenylation sequence within exon 3 of DUX4 that stabilizes pathogenic transcripts, and the loss of repressive chromatin modifications at D4Z4, the macrosatellite repeat which encodes DUX4.
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Repression of repetitive elements is crucial to preserve genome integrity and has been traditionally ascribed to constitutive heterochromatin pathways. FacioScapuloHumeral Muscular Dystrophy (FSHD), one of the most common myopathies, is characterized by a complex interplay of genetic and epigenetic events. The main FSHD form is linked to a reduced copy number of the D4Z4 macrosatellite repeat on 4q35, causing loss of silencing and aberrant expression of the D4Z4-embedded DUX4 gene leading to disease.
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Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.
We looked at a disease-associated macrosatellite array D4Z4 and focused on epigenetic factors influencing its chromatin state outside of the disease-context. We used the HCT116 cell line that contains the non-canonical polyadenylation (poly-A) signal required to stabilize somatic transcripts of the human double homeobox gene DUX4, encoded from D4Z4. In HCT116, D4Z4 is packaged into constitutive heterochromatin, characterized by DNA methylation and histone H3 tri-methylation at lysine 9 (H3K9me3), resulting in low basal levels of D4Z4-derived transcripts.
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