Evaluating LINE-1 Methylation in Cleft Lip Tissues and its Association with Early Pregnancy Exposures

Khan, Mohammad Faisal Jamal; Little, Julian; Mossey, Peter; Steegers‐Theunissen, R.P.M.; Autelitano, Luca; Lombardo, Ilenia; Andreasi, Rita Bassi; Rubini, Michele

doi:10.2217/epi-2017-0081

Cited by 16 publications

(18 citation statements)

References 60 publications

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“…The observed differences in methylation could be manifested as a sustained response, which is in line to our previous hypothesis (Khan et al, ) of these tissues experiencing different maternal environment to which they are highly responsive, and thus providing an insight into epigenetic effects of early life environmental exposures (Richmond & Joubert, ).…”

Section: Discussionsupporting

confidence: 89%

“…The medial and lateral tissues of upper lip structure originate from distinct and at slightly different embryonic periods, and are thereby susceptible to aberrant maternal environmental exposure(s). Some empirical support is provided by our recent study showing methylation reprogramming within these tissues (Khan et al, 2018) in infants with non-syndromic cleft lip and palate (nsCL/P). This has increased considerable interest to identify factors that determine the pattern of methylation in tissues from medial and lateral aspects of the upper lip.…”

Section: Introductionmentioning

confidence: 79%

“…Studies investigating the role of epigenetic variation in the etiology of non‐syndromic orofacial clefts have recently begun to emerge in humans (Alvizi et al, ; Khan et al, ; Sharp et al, ). There are, however, no reports of the effect of the MTHFR c.677C>T variant on LINE‐1 methylation and nsCL/P etiology.…”

Section: Introductionmentioning

confidence: 99%

“…Studies investigating the role of epigenetic variation in the etiology of non-syndromic orofacial clefts have recently begun to emerge in humans (Alvizi et al, 2017;Khan et al, 2018;Sharp et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

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LINE‐1 methylation in cleft lip tissues: Influence of infant MTHFR c.677C>T genotype

et al. 2019

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Objective To investigate the influence of MTHFR c.677C>T genotype on LINE‐1 methylation in lateral and medial tissues from cleft lip (CL). Methods Forty‐five consecutive non‐syndromic cleft lip with or without cleft palate (nsCL/P) cases were included in the study. Genomic DNA was extracted from tissues at both sides of cleft lip, and LINE‐1 methylation was detected by bisulfite conversion and pyrosequencing. MTHFR c.677C>T genotyping was carried out using the TaqMan genotyping assay. Results LINE‐1 methylation level was significantly higher on medial side of cleft lip compared with lateral side (p = 0.001). This difference was not significantly influenced by the case's sex or cleft type. However, MTHFR c.677C>T genotyping revealed that the difference in LINE‐1 methylation across cleft lip was restricted to carriers of C allele of MTHFR c.677C>T and was not apparent in TT homozygous cases (p = 0.027). Conclusion This integrated analysis supports the previous finding of differences in DNA methylation across the two sides of cleft lip and further suggests a possible role of MTHFR c.677C>T genotype in establishing this difference.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LINE‐1 methylation in cleft lip tissues: Influence of infant MTHFR c.677C>T genotype

et al. 2019

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“…The average age of cases at the time of first lip surgery was eight months (95% CI 4.6–11.4). The samples were collected at the Regional Centre for Orofacial Clefts and Craniofacial Anomalies, San Paolo Hospital, Milan, Italy in the framework of the PENTACLEFT project (Khan et al, ; Khan, Little, Abelli, Mossey, et al, ; Khan, Little, Mossey, Steegers‐Theunissen, Bonsi, et al, ), which was approved by local IRB (prot. N.08‐2011).…”

Section: Methodsmentioning

confidence: 99%

Ultrastructural analysis of collagen fibril diameter distribution in cleft lip

et al. 2018

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MTHFR promoter methylation might mitigate the effect of smoking at the level of LINE‐1 in cleft lip tissues: A preliminary study

Khan

Little

Mossey

et al. 2021

Birth Defects Research

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Background: The medial and maxillary aspects of the upper lip originate at separate embryonic stages and therefore may experience different maternal exposure patterns which may affect methylation. Based on this hypothesis, we investigated the level of methylation of the methylene tetrahydrofolate reductase promoter gene (mMTHFR) in tissues from cleft lip, and mMTHFR levels by MTHFR c.677C > T genotype. We further investigated whether mMTHFR mitigates the effect of smoking on long interspersed nuclear element (LINE-1) methylation in these tissues.Methods: DNA extracted from medial and lateral tissues of 26 infants with nonsyndromic cleft lip with or without cleft palate (nsCL/P) was bisulfite converted and mMTHFR was measured on a pyrosequenser. LINE-1 methylation and MTHFR c.677C > T genotype data were obtained in our previous study.Results: There was no substantial difference in mMTHFR (p = .733) and LINE-1 (p = .148) between the two tissues. mMTHFR was not influenced by MTHFR c.677C > T genotype, but there was suggestive evidence that the difference was larger among infants exposed to maternal smoking compared to nonexposed. LINE-1 methylation differences were significant (p = .025) in infants born to nonsmoking mothers, but this was not apparent (p = .872) in infants born to mothers who smoked. Our Pearson's correlation analysis suggested a weak inverse association between mMTHFR and LINE-1 (r = À.179, p = .381). Conclusion:Our preliminary observation of differences in patterns of mMTHFR levels in lip tissue suggests the interplay of gene and environment in the establishment of methylation in tissues at both sides of cleft lip. This requires investigation in a larger cohort, integrated with metabolic assessment.

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Evaluating LINE-1 Methylation in Cleft Lip Tissues and its Association with Early Pregnancy Exposures

Abstract: The observed differences in DNA methylation, although nonsignificant after correction for multiple comparisons, suggest that differential regulation of the two sides may impact lip fusion and warrant larger-scale replication.

Cited by 16 publications

References 60 publications

LINE‐1 methylation in cleft lip tissues: Influence of infant MTHFR c.677C>T genotype

LINE‐1 methylation in cleft lip tissues: Influence of infant MTHFR c.677C>T genotype

Ultrastructural analysis of collagen fibril diameter distribution in cleft lip

MTHFR promoter methylation might mitigate the effect of smoking at the level of LINE‐1 in cleft lip tissues: A preliminary study

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