Alterations in DNA Methylation in Orofacial Clefts
Abstract
:1. Introduction
2. Alterations in DNA Methylation Found in Blood Samples of Patients with anOrofacial Cleft
3. Alterations in DNA Methylation Found in Lip, Palate, and Saliva of Patients with an Orofacial Cleft
4. Alterations in DNA Methylation in Animals with a Genetically Induced Orofacial Cleft
5. Alterations in DNA Methylation in Animals with a Genetically Induced Orofacial Cleft
6. Limitations and Strengths
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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Samples (Population) | Number of Cases: Gender (Controls: Gender) | Major Findings in Methylation | Interpretation | Ref | ||||
---|---|---|---|---|---|---|---|---|
Gene (Chromosome) | CpG | DMR | Methylation Level (%) | Risk of Orofacial Cleft | ||||
Whole blood (Brazil) Whole blood (UK) | 67 CL/P: M = 37, F = 30 (59: M = 28, F = 31) 171 CL/P: M = 107, F = 64 (177: M = 100, F = 77) | (Chr8) (Chr4) (Chr1) (Chr4) | cg00611675 cg00405769 cg15897635 cg03150409 | MYC FAT1 Chr1 WHSC1 | ↓ ↓ ↓ ↓ | NA | Hypomethylation at MYC, FAT1, Chr1, WHSC1 contributed to CLP. | Alvizi et al., 2017 [18] |
Leukocytes (UK) | Total 150: 50 CLO: M = 31, F = 19 50 CPO: M = 27, F = 23 50 CL/P: M = 42, F = 8 (-) | TBX1(Chr22) COL11A2 (Chr6) HOXA2 (Chr7) CRB2 (Chr9) PDGFRA (Chr4) CRISPLD2 (Chr16) SMOC1 (Chr14) PVRL1 (Chr11) CCL2 (Chr17) | 6 15 7 2 2 2 5 2 6 | 19750918–19752870 33132086–33132728 27143046–27143807 126130901–126131310 55090812–55091179 84870066–84870204 70316898–70317240 119630144–119630]3 32582128–32582829 | ↑ CPO vs. CLO ↑ CPO vs. CLO ↑ CPO vs. CLO, CL/P ↑ CPO vs. CLO ↑ CPO vs. CLO ↑ CPO vs. CLO ↓ CPO vs. CL/P ↓ CPO vs. CLO ↓ CPO vs. CLO | NA | Methylation level associated with orofacial cleft subtype, mostly CPO, was hypermethylated to a greater extent than CLO (dependent on regions of methylation). | Sharp et al., 2017 [25] |
Leukocytes (China) | Total 37: M = 28, F = 9 20 CL/P: - 17 CLO: - (60: M = 40, F = 20) | LINE-1 (-) IRF-6 (-) | L1_11.12 I6_34.35 | NA NA | Total (↑ 1.78%) >CL/P (↑ 1.77%) >CLO (↑ 1.75%) >control CL/P (↑ 3.42%) >Total (↑ 2.99%) >CLO (↑ 2.48%) >control | OR: ↑ CLO 12.07 OR: ↑ Total 6.89 OR: ↑ CL/P 4.83 OR: ↑ CL/P 6.00 OR: ↑ Total 4.67 OR: ↑ CLO 3.60 | Hypermethylation of LINE-1 and IRF-6 increased CL/P risk. | Li et al., 2019 [21] |
Whole blood (UK) | Central European: 399 CL/P: - (1318: -) European ICC duos/trios: 816 CL/P: - (1454: -) | VAX1 (-) NTN1 (-) LOC146880 (-) | cg11398452 cg16197528 cg02598441 | NA | ↓ ↓ ↑ | Mediation causal effect: SNP → DNA methylation → CL/P | Genetic variants caused hypomethylation of VAX1 and NTN1 and hypermethylation of LOC146880; both induced CL/P. | Howe et al., 2019 [19] |
Whole blood (Norway) | 92 CLO: M = 51, F = 41; 84 CPO: M = 37, F = 47; 132 CL/P: M = 95, F = 37 (436: M = 238, F = 198) | BICC1 (Chr10) (CLO + CL/P) CLASRP (Chr9) (CPO + CL/P) | cg09696939 cg26985354 | 26 31 | ↓ (average 0.02) ↑ (average 0.89) | NA NA | BICC1 hypermethylation was associated with cleft lip subtype; CLASRP hypomethylation was associated with cleft palate subtype. | Xu et al., 2019 [20] |
Samples (Population) | Number of Cases (Controls) | Major Findings in Methylation | Interpretation | Ref | |||
---|---|---|---|---|---|---|---|
Gene (Chromosome) | CpG (DMR) | Methylation Level (%) | Correlation with Blood Methylation | ||||
Lip (UK) | 18 CL/P lip (18 CL/P blood from same individuals) | NA | NA | NA | Highly positive | A correlation was shown between methylation and lip and blood samples | Alvizi et al., 2017 [18] |
Lip (UK) Palate (UK) | 48 CLO (43 CL/P) 7 CPO (43 CL/P) | LOC154882 (Chr7) PARK2 (Chr6) OR2L13 (Chr1) KIAA0415 (Chr7) VAMP3 (Chr1) NA | - (158789723–158790116) - (161796785–161796855) - (248100183–248100615) - (4832112–4832536) - (7842159–7842407) NA | NA NA NA CLO 4% > CL/P NA NA | 84% positive 73% positive | Blood methylation levels showed a strong correlation with tissue-specific cleft subtype: - Between blood and lip in CLO - Between blood and palate in CPO | Sharp et al., 2017 [25] |
Lip (China) | Total 23 CL 13 CL/P 10 (-) | LINE-1 (-) | NA | Medial > lateral (↑1.87%) | NA | Two separated embryologic origins and timing of development of CL caused LINE-1 methylation profile differences in which the medial side was hypermethylated more than the lateral side. | Khan et al., 2018 [26] |
Lip (China) | 45 CL/P: 23 left, 6 right, 7 bilateral (-) | LINE-1 (-) MTHFR c.677C > T genotype -CC -CT -TT | NA | Medial > lateral (↑4.3%) Medial > lateral (↑3.14%) ↔ | NA | LINE-1 methylation in the medial side of CL was hypermethylated to a greater extent than the lateral side, which was possibly influenced by MTHFR c.677C > T (C allele). | Khan et al., 2019 [27] |
Saliva (US) | 6 affected CLP twin (6 unaffected normal twin) | MAFB (Chr20) ZEB2 (Chr2) | NA | ↓ | NA | Comparison of differential methylation between monozygotic twin pairs discordant for NSCLP found hypomethylation in MAFB and ZEB2. | Young et al., 2021 [34] |
Animal Model Cases (Control) | Number of Cases (Control) | Age of Embryo (Organ Specificity) | Major Findings in Methylation | Interpretation | Ref | ||
---|---|---|---|---|---|---|---|
Gene (Chromosome) | Transcription Level | Methylation Level (Mean %) | |||||
A/WySn mice, C57BL/6J mice (-) | 1146 (-) | E14 (lip formation) | Clf2 (Chr13) Genotype BB, AB, AA | NA | BB > AB > AA A/WySn lip phenotype - ↑ Normal lip (30–60%) -↓ CL/P (0–20%) | - Clf2 gene polymorphism, especially in A allele, induced hypomethylation and an increased risk of CL/P in A/WySn mice strain. - Severity of lip phenotype varied throughout methylation levels of Clf2 (lower methylation directly correlated with increased severity of lip phenotypes). | Plamondon et al., 2011 [41] |
A/WySn mice (C57BL/6J mice as normal strain) | Transcription level - 13/ (6) Methylation level - 12/ (10) | E10 (nasal pit invagination) E11 (medial and lateral prominence expansion) E12 (primary palate formation) | Wnt9b (Chr11) | A/WySn < C57BL/6J 1.6 fold A/WySn < C57BL/6J 2.2 fold A/WySn < C57BL/6J 1.5 fold | ↓ Overall A/WySn lip phenotype (compared with C57BL/6J) - ↑ Normal lip (50%) - ↓ Unilateral CL (10–40%) - ↓↓ Bilateral CL (0%) | - A/WySn mice had low Wnt9b transcription level and increased risk of CL. - Hypomethylation of Wnt9b was correlated with the severity of CL phenotypes (lower methylation was associated with more severe phenotypes). | Juriloff et al., 2014 [42] |
A/WySn mice (-) | 50 (-) | E11 (medial nasal process) | Wnt9b (Chr11) | NA | ↓ (0–20%) | Hypomethylation at Wnt9b in A/WySn mice nonlinearly affected facial shape variation in CLP (lower methylation was associated with increased facial shape variation). | Green et al., 2019 [37] |
Species /Organ Specificity (Age) /Population | Risk Factors /Exposure duration /Vehicle | Number of Cases (Control) | Major Findings in Methylation | Interpretation | Ref | |||
---|---|---|---|---|---|---|---|---|
Gene (Chromosome) | CpG (DMR) | Gene Expression Level (Fold Change) | Methylation Level (% Change) | |||||
ICR mice (normal strain) /1st branchial arch cultured cell (E10.5) /- | Cigarette smoke extract (CSE) 20 mcg/mL 40 mcg/mL 80 mcg/mL /24 h /Phosphate-buffered saline Proteasome inhibitor (MG-132) 1.5 mcM /3 h prior to 24 h of CSE /Dimethyl sulfoxide | NA NA | Overall Overall Overall DNMT-1 (-) DNMT-3A (-) DNMR-3B (-) MeCP-2 (-) MBD-2 (-) MBD-3 (-) DNMT-1 (-) DNMT-3A (-) MeCP-2 (-) MBD-3 (-) | NA NA | NA NA NA ↓ 2.21 ↓ 1.85 ↓ 1.80 ↓ 2.43 ↓ 1.50 ↓ 1.52 ↑ ↑ ↑ ↑ | ↔ ↓ 1.8 % ↓ 13% NA NA NA NA NA NA NA NA NA NA | Cigarette smoke extract decreased overall gene expression level of DNA methyltransferase and methyl-CPG-binding domain protein, leading to global DNA hypomethylation in a dose-dependent manner, which induced occurrence of CLP. Pretreatment with proteasomal inhibitor can reverse global DNA methyltransferase and methyl-CPG-binding domain protein degradation from cigarette smoke extract via inhibition of the proteomic degradation pathway. | Mukhopadhyay et al., 2015 [43] |
C57BL/6J mice (normal strain) /palatal shelves (E14.5) /- | All-trans retinoic acid 70 mg/kg /4 days oral gavage /corn oil | 3 (3) | HDAC4 (-) SMAD3 (-) MID1 (-) | 92051600–92053400 63658601–63660200 169978000–169980801 | NA | ↑ ↑ ↓ | All-trans retinoic acid caused hypermethylation of both HDAC4 and SMAD3 and hypomethylation of MID1, which disrupted palatogenesis, resulting in an increased risk of CP. | Shu et al., 2018 [46] |
C57BL/6J mice (normal strain) /palatal shelves (E14.5) /- | All-trans retinoic acid 70 mg/kg /oral gavage /corn oil | 3 (3) | Fgf16 (ChrX) Tbx22 (-) | 105725515–105764278 CCGG exon sequences | ↓ ↓ | ↑ ↑ | All-trans retinoic acid caused reciprocal relation (hypermethylation but decreased gene expression) of Fgf16 and Tbx22, which caused developmental failure of the palate, leading to CP. | Shu et al., 2019 [38] |
Human /newborn archived bloodspot /USA | Without folic acid (prior to mandatory folate dietary) /- /- | 94 CL/P: M = 57, F = 37 (88: M = 51, F = 37) | NA ZNF77 (Chr19) EDH2 (Chr19) VTRNA2-1 (-) LHX8 (Chr1) MIR140 (Chr16) WNT9B (Chr17) | 63.5% of overall CpG cg19689947 cg02718229 NA NA NA NA | NA | ↓ ↓↓ ↓↓ ↓ ↓ ↑ ↑ | Periconceptional folic acid deficiency induced widespread hypomethylation, except hypermethylation of MIR140 and WNT9B, which increased the risk of CL/P. | Gonseth et al., 2019 [51] |
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Charoenvicha, C.; Sirimaharaj, W.; Khwanngern, K.; Chattipakorn, N.; Chattipakorn, S.C. Alterations in DNA Methylation in Orofacial Clefts. Int. J. Mol. Sci. 2022, 23, 12727. https://doi.org/10.3390/ijms232112727
Charoenvicha C, Sirimaharaj W, Khwanngern K, Chattipakorn N, Chattipakorn SC. Alterations in DNA Methylation in Orofacial Clefts. International Journal of Molecular Sciences. 2022; 23(21):12727. https://doi.org/10.3390/ijms232112727
Chicago/Turabian StyleCharoenvicha, Chirakan, Wimon Sirimaharaj, Krit Khwanngern, Nipon Chattipakorn, and Siriporn C. Chattipakorn. 2022. "Alterations in DNA Methylation in Orofacial Clefts" International Journal of Molecular Sciences 23, no. 21: 12727. https://doi.org/10.3390/ijms232112727