Cognitive benefits of folic acid supplementation during pregnancy track with epigenetic changes at an imprint regulator
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".