Epigenetics of Myotonic Dystrophies: A Minireview
Abstract
:1. Introduction
2. Genetics of Myotonic Dystrophies
3. Methylation of DMPK and CNBP Genes
4. Chromatin Remodeling of DM1 Locus
5. miRNAs-Based Mechanisms of Epigenetic Regulation in DMs
5.1. Tissue-Specific miRNAs Deregulated in DMs
5.2. Circulating miRNAs Deregulation in DMs
6. Clinical Significance of Epigenetic Signatures in DMs
7. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Disease Form | Tissue | Sample Size | Genomic Context (DMPK Gene) | Method of Analysis | Analysis Outcome | Reference |
---|---|---|---|---|---|---|
CDM1; Adult | Dura mater, skeletal muscle, skin biopsies and white blood cells | 30 DM1 | Upstream region of (CTG)n repeats, corresponding to the genomic SacI-HindIII fragment carrying exons 11–15 | Methylation-sensitive restriction enzymes digestion | Hypermethylation in intron 12 at restriction sites of SacII and HhaI in CDM1 patients | [35] |
DM1 foetuses; DM1 adults; Transgenic DM1 mice | Different source | 13 DM1 vs. 3 CTRs | CTCF binding sites upstream and downstream of the CTG repeats | Bisulphite-sequencing PCR and methylation-sensitive restriction enzymesdigestion | Hypermethylation of upstream sequences in DM1 individuals. In DM1, mice methylation pattern was present up- and down-stream of the CTG array | [40] |
Childhood-onset; Juvenile/adult-onset; CDM1 with uninterrupted CTG expansions; DM1 “atypical” | Whole blood | 66 DM1 including 9 patients with VRs vs. 30 CTRs | DNA sequences (including CTCF-1 and CTCF-2) in 5′ and in 3′ end regions of the CTG array | MS-HRM | Hypermethylation of upstream sequences in CDM1 and childhood-onset patients with large uninterrupted (CTG)n expansions, significantly associated with maternal transmission. First evidence that DM1 patients with VRs show a distinctive hypermethylation pattern at 3′ end of the CTG array | [27] |
Premutated DMPK alleles containing VRs | Whole blood | Three-generation Italian family | DNA sequences (including CTCF-1 and CTCF-2) in 5′ and in 3′ end regions of CTG array | Pyrosequencing | Absence of an in cis effect of the (CCG)n interruptions on the methylation of the DM1 locus | [43] |
DM1-Affected hESC Line Collection | hESCs | 14 DM1 | DNA sequence spanning from exon 11 to the CTG repeats | Pyrosequencing | Marked increase in methylation levels of the expanded allele | [39] |
Late-onset; Adult; Juvenile; Childhood | Whole blood | 92 DM1 vs. 10 CTRs | Upstream (CTCF1) and downstream (CTCF2) regions | Sanger Sequencing and Massive Parallel Sequencing | DNAme levels of both CTCF sites higher in CDM1 than in non-CDM1 patients | [34] |
Adult-onset; DM1 “atypical” | Whole blood | 90 DM1 including 8 patients with VRs | CpG sites upstream and downstream of the (CTG)n expansion | Pyrosequencing | DNAme levels upstream of the (CTG)n expansion were correlated with CTG repeat length, and the presence of a VRs was associated with higher DNAme levels compared to pure CTG array | [42] |
Adult-onset; DM1 “atypical” | Whole blood | 115 DM1 including 12 patients with VRs | Downstream region (no CTCF binding sites) of the (CTG)n repeats | Pyrosequencing | Patients with VRs alleles had distinctive DNAme and cognitive profiles | [28] |
Noncongenital DM1 | Whole blood | 68 DM1 vs. 73 CTRs | Upstream and downstream regions (no CTCF binding sites) of the (CTG)n repeats | Pyrosequencing | Hypermethylation of both upstream and downstream regions | [44] |
DM2 | Whole blood | 72 DM2 vs. 50 CTRs | CpG islands in the 5′ promoter region and in the region 3′ of the [CCTG]n repetitions | Pyrosequencing | No significant differences in the methylation profile between DM2 patients and CTRs | [45] |
Skeletal muscle | 7 DM2 vs. 7 CTRs | |||||
Skeletal muscle | 7 DM2 vs. 7 CTRs |
miRNA | Sample Type DM1 | Sample Size | Analysis Outcome (Up or Down Regulation) | Reference |
---|---|---|---|---|
miR-206 | Skeletal muscle (vastus lateralis) | 7 DM1 vs. 4 CTR | Up | [64] |
[miR-1; miR-335 miR-33] | Skeletal muscle (biceps branchii) | 15 DM1 vs. 14 CTR | [Up] | [65] |
miR-29b/c | Down | |||
miR-1; miR-7; miR-10 | Skeletal muscle (vastus lateralis, biceps branchii, deltoid) | 5 DM1 vs. 3 CTR | Down | [66] |
miR-206 | Skeletal muscle (vastus lateralis) | 12 DM1 vs. 6 CTR | Up | [67] |
[miR-1; miR-133a/b] | [Down] | |||
miR-1; miR-133a; miR-29c | Skeletal muscle (biceps branchii, deltoid, Gastrocnemium) | 9 DM1 Vs. 9 CTR | Down | [68] |
miR-1 | Heart | 5 DM1 vs. 8 CTR | Down | [69] |
miR-1; miR-133; miR-29b; miR-30b; miR-145; let-7d/g; miR-23a/b; miR-26a; miR-328; miR-365; miR-499; miR-125b; miR-148°; miR-194; miR-27a; miR-22; miR-100 | Heart | 8 DM1 vs. 4 CTR | Down | [70] |
[miR-113a; miR-193b; miR-191; miR-454; miR-574; miR-885-5p; miR-886-3p] | Plasma | 36 DM1 vs. 36 CTR | [Up] | [71] |
miR-27b | Down | |||
[miR-1; miR-133a/b; miR-206; miR-140-3p; miR-454; miR-574] | Plasma | 103 DM1 vs. 111 CTR | [Up] | [72] |
miR-27b | Down | |||
miR-1; miR-133a/b; miR-206 | Serum | 23 DM1 vs. 23 CTR | Up | [73] |
miR-1; miR-133a/b; miR-206; miR-113a; miR-193b; miR-191; miR-574; miR-885-5p; miR-886-3p; miR-27b | Serum | 63 DM1 vs. 63 CTR | Up | [74] |
miR-1; miR-133a/b; miR-206 | Serum | 9 DM1 vs. 7 CTR | Up | [75] |
miR-133a; miR-29b; miR-33a | Whole blood | 10 DM1 vs. 10 CTR | Up | [68] |
miR-1 | Heart | 2 DM2 vs. 8 CTR | Down | [69] |
[miR-34a-5p; miR-34b-3p; miR-34c-5p; miR-146b-5p; miR-208a; miR-221-3p; miR-381] | Skeletal muscle (biceps brachi) | 13 DM2 vs. 13 CTR | [Up] | [76] |
miR-125b-5p, miR-193a-3p, miR-193b-3p and miR-378a-3p | Down | |||
miR-1; miR-133a/b; miR-206; miR-140-3p; miR-454; miR-574 | Plasma | 30 DM2 vs. 111 CTR | Up | [72] |
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Visconti, V.V.; Centofanti, F.; Fittipaldi, S.; Macrì, E.; Novelli, G.; Botta, A. Epigenetics of Myotonic Dystrophies: A Minireview. Int. J. Mol. Sci. 2021, 22, 12594. https://doi.org/10.3390/ijms222212594
Visconti VV, Centofanti F, Fittipaldi S, Macrì E, Novelli G, Botta A. Epigenetics of Myotonic Dystrophies: A Minireview. International Journal of Molecular Sciences. 2021; 22(22):12594. https://doi.org/10.3390/ijms222212594
Chicago/Turabian StyleVisconti, Virginia Veronica, Federica Centofanti, Simona Fittipaldi, Elisa Macrì, Giuseppe Novelli, and Annalisa Botta. 2021. "Epigenetics of Myotonic Dystrophies: A Minireview" International Journal of Molecular Sciences 22, no. 22: 12594. https://doi.org/10.3390/ijms222212594