Hypermethylation and Transcriptional Alterations Drive CDM
Increasing evidence has established a role for epigenetic events in pathogenesis of CDM. Methylation at CpG sites upstream of the DMPK locus has been linked to the etiology of CDM, as well as to the maternal bias of its inheritance (Barbé et al., 2017). Moreover, hypermethylation at this locus has been modeled as a key differentiator of the CDM vs. DM1 clinical phenotype (Lanni and Pearson, 2019).
Does DMPK Methylation Also Modulate DM1 Phenotypes?
The degree to which epigenetic events that have been linked to CDM could also play a role in DM1 severity is unclear. Dr. Luigi Bouchard (Université de Sherbrooke) and colleagues sought to determine whether DNA methylation around DMPK-expanded repeat tracts could impact DM1 phenotypes (Légaré et al., 2019).
The research team studied 90 patients with the adult form of DM. Expanded CTG repeat length, DMPK methylation at 8 distinct CpG island loci (designated L1-L8), muscle strength (by dynamometer), and pulmonary function (FVC, PEF, MIP, and MEP) were evaluated. Relationships between patient molecular and functional parameters were assessed using stepwise multiple linear regression analyses.
CTG repeat length correlated with methylation level, but in opposite directions for upstream vs. downstream CpG sites. The presence of variant repeats in the CTG tract was associated with higher methylation at downstream, but not at upstream, sites. Data showed that CpG site methylation at the expanded repeat DMPK locus explained variability in muscle strength and respiratory function profiles independent of expanded CTG repeat length. Specifically, a downstream (L6 site) epigenetic modification contributed to variability in ankle dorsiflexion, grip, and pinch strengths, as well as to FVC and MIP. Moreover, methylation levels were associated with somatic instability of the CTG repeat (difference of average and progenitor repeat length), but not with symptom onset age.
Potential Mechanism of Action of Methylation at DM1 Locus
Due to variability in affected muscle groups, the research team suggested that methylation at specific CpG sites might alter affinity of specific transcription factors, but using binding site analysis could not identify any particular transcription factor. They suggest that methylation could underlie variability of DM1 phenotypes via: (a) blockage of CTCF binding, (b) reduction of DMPK and SIX5 transcription, and/or (c) alteration of CTG repeat instability. Finally, the authors suggest that assessment of DNA methylation at the pathogenic DMPK locus may have prognostic value to guide patient care.
CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy.
Barbé L, Lanni S, López-Castel A, Franck S, Spits C, Keymolen K, Seneca S, Tomé S, Miron I, Letourneau J, Liang M, Choufani S, Weksberg R, Wilson MD, Sedlacek Z, Gagnon C, Musova Z, Chitayat D, Shannon P, Mathieu J, Sermon K, Pearson CE.
Am J Hum Genet. 2017 Mar 2;100(3):488-505. doi: 10.1016/j.ajhg.2017.01.033.
Molecular genetics of congenital myotonic dystrophy.
Lanni S, Pearson CE.
Neurobiol Dis. 2019 Jul 18:104533. doi: 10.1016/j.nbd.2019.104533. [Epub ahead of print] Review.
DMPK gene DNA methylation levels are associated with muscular and respiratory profiles in DM1
Légaré C, Overend G, Guay SP, Monckton DG, Mathieu J, Gagnon C, Bouchard L.
Neurol Genet. 2019 May 23;5(3):e338. doi: 10.1212/NXG.0000000000000338. eCollection 2019 Jun.