Cognitive benefits of folic acid supplementation during pregnancy track with epigenetic changes at an imprint regulator.

Autor: Hilman L; School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK., Ondičová M; School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK.; Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada., Caffrey A; Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK., Clements M; Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK., Conway C; School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK., Ward M; Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK., Pentieva K; Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK., Irwin RE; School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK., McNulty H; Nutrition Innovation Centre for Food and Health (NICHE), School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK., Walsh CP; School of Biomedical Sciences, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, BT52 1SA, UK. colum.walsh@liu.se.; Department for Cell and Neurobiology, Biomedical and Clinical Sciences Division, Faculty of Medicine, Linköping University, 581 83, Linköping, Sweden. colum.walsh@liu.se.
Jazyk: angličtina
Zdroj: BMC medicine [BMC Med] 2024 Dec 16; Vol. 22 (1), pp. 579. Date of Electronic Publication: 2024 Dec 16.
DOI: 10.1186/s12916-024-03804-2
Abstrakt: Background: The human ZFP57 gene is a major regulator of imprinted genes, maintaining DNA methylation marks that distinguish parent-of-origin-specific alleles. DNA methylation of the gene itself has shown sensitivity to environmental stimuli, particularly folate status. However, the role of DNA methylation in ZFP57's own regulation has not been fully investigated.
Methods: We used samples and data from our previously described randomised controlled trial (RCT) in pregnancy called Folic Acid Supplementation in the Second and Third Trimester (FASSTT), including follow-up of the children at age 11. Biometric and blood biochemistry results were examined for mothers and children. Methylation of ZFP57 was analysed by EPIC arrays, pyrosequencing and clonal analysis, and transcription assessed by PCR-based methods. Functional consequences of altered methylation were examined in cultured cells with mutations or by inhibition of the main DNA methyltransferases. DNA variants were examined using pyrosequencing and Sanger sequencing, with results compared to published studies using bioinformatic approaches. Cognitive outcomes were assessed using the Wechsler Intelligence Scale for Children 4th UK Edition (WISC-IV), with neural activity during language tasks quantified using magnetoencephalography (MEG).
Results: Here we show that methylation at an alternative upstream promoter of ZFP57 is controlled in part by a quantitative trait locus (QTL). By altering DNA methylation levels, we demonstrate that this in turn controls the expression of the ZFP57 isoforms. Methylation at this region is also sensitive to folate levels, as we have previously shown in this cohort. Fully methylated alleles were associated with poorer performance in the Symbol Search and Cancellation subtests of WISC-IV in the children at age 11 years. There were also differences in neural activity during language tasks, as measured by MEG. Analysis of published genome-wide studies indicated other SNPs in linkage disequilibrium with the mQTL were also associated with neurodevelopmental outcomes.
Conclusions: While numbers in the current RCT were small and require further validation in larger cohorts, the results nevertheless suggest a molecular mechanism by which maternal folic acid supplementation during pregnancy may help to counteract the effects of folate depletion and positively influence cognitive development in the offspring.
Competing Interests: Declarations. Ethics approval and consent to participate: The Office for Research Ethics Committee for Northern Ireland (ORECNI) has granted ethical approval for the original randomised controlled FASSTT trial (ref:05/Q2008/21) and for the follow-up FASSTT Offspring Trial (12/NI/0077). Ulster University Research Ethics Committee also approved the FASSTT Off spring Trial (UUREC: 12/0121). Written informed consent from the mother and assent from the child were obtained. The trials were registered at ISRCTN Registry (ISRCTN19917787). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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