SMCHD1 is involved inde novomethylation of theDUX4-encoding D4Z4 macrosatellite

Abstract

The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation.

Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy

“…It has to be noted that SMCHD1 variants as well as D4Z4 hypomethylation in the presence of the haplotype 4qA/PAS distal to the D4Z4 array have been found in patients with bosma arhinia and microphtalmia syndrome, a congenital disease with no associated muscle phenotype. [5][6][7][8][9][10][11][12] The classic FSHD phenotype is characterized by onset in the first or second decade of life with progressive facial, shoulder girdle, and pectoral muscle weakness and atrophy, often asymmetric. 13 Disease progression may lead to the involvement of abdominal muscles and distal lower extremity weakness, causing a steppage gait before impairment of pelvic girdle muscles.…”

Type 1 FSHD with 6–10 Repeated Units: Factors Underlying Severity in Index Cases and Disease Penetrance in Their Relatives Attention

“…FSHD severity and DNA methylation. It recently became evident that the SMCHD1 epigenetic modifier has a role in FSHD [29], as well as in the regulation of D4Z4 methylation [30]. Although we did not evaluate methylation in all patients, hypomethylation was overall more significant in patients randomly selected in the two subgroups tested, i.e., patients with a high severity score (CSS >3.5) as compared to patients with a low severity score (CSS <1.5), particularly for the proximal D4Z4 region (DR1 and 5P).…”

Does DNA Methylation Matter in FSHD?

“…This argues for the presence of two mechanisms acting at D4Z4 upon reprogramming: an active "erasure" of the cell-of-origin epigenetic profile and a "rewriting" of a de novo methylation pattern at the array. Moreover, reports demonstrate that the D4Z4 methylation was identical from clone to clone from both FSHD1 patients and controls, indicating that remethylation of D4Z4 upon epigenetic reprogramming does not depend on the residual number of D4Z4 repeats [79].…”

“…The higher methylation level found at D4Z4 in pluripotent cells further suggests that D4Z4 methylation status does not correlate with the number of repeats but is a feature of stemness, which highlights once more the complex but yet unknown regulatory mechanisms of this locus [79].…”

“…More strikingly, considering the clinical phenotype, the marked D4Z4 hypomethylation detected in the majority of FSHD2 patients carrying a mutation in SMCHD1 is not accompanied either with a more severe phenotype or earlier disease onset. Moreover, D4Z4 hypomethylation, in the presence of the haplotype 4qA/PAS distal to the D4Z4 array, which is considered permissive of DUX4 expression, is not associated with a muscle phenotype in patients with Bosma Arhinia and Microphthalmia syndrome (BAMS), patients affected with ICF (Immunodeficiency, Centromeric Instability, and Facial anomalies) homozygotes for DNMT3B mutation and their heterozygote parents [78], or patients carrying a deletion of the 18p chromosome containing the SMCHD1 gene [79]. Besides, in the few families with FSHD index cases carrying a mutation in DNMT3B [47] or an 18p deletion [80], the presence of a DNA mutation and D4Z4 hypomethylation does not segregate with clinical signs of the disease.…”