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Updated: Oct 8, 2025
Author Spotlight: Studying the Impact of Maternal Dietary Deficiencies on Long-Term Offspring Health Outcomes
Published on: June 28, 2024
Prenatal Iron Deficiency and Choline Supplementation Interact to Epigenetically Regulate Jarid1b and Bdnf in the Rat
Shirelle X Liu1,2, Amanda K Barks1, Scott Lunos3
1Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
Insights
Early iron deficiency causes lasting cognitive issues by altering gene regulation via JARID1B. Prenatal choline supplementation did not prevent this but had separate, potentially negative, epigenetic effects.
Area of Science:
- Neuroscience
- Epigenetics
- Developmental Biology
Background:
- Early-life iron deficiency (ID) leads to persistent neurocognitive deficits and gene dysregulation.
- Prenatal choline supplementation may partially mitigate these effects, but the underlying mechanisms are unclear.
Purpose of the Study:
- To investigate the epigenetic mechanisms by which iron and choline influence long-term gene dysregulation following early-life ID.
- To examine the role of JARID1B and BDNF in ID-induced cognitive dysfunction and the impact of choline supplementation.
Main Methods:
- Utilized a rat model of fetal-neonatal iron deficiency.
- Assessed hippocampal gene expression, histone modifications (H3K9ac, HDAC1), and transcription factor enrichment (pCREB).
- Analyzed the impact of ID and prenatal choline supplementation on JARID1B and BDNF regulation.
Main Results:
- ID downregulated hippocampal JARID1B, an iron-dependent histone demethylase, leading to increased HDAC1 and decreased H3K9ac and pCREB.
- ID reduced BDNF transcriptional capacity, with decreased H3K9ac and pCREB at BDNF promoters.
- Choline supplementation did not reverse ID-induced chromatin changes but induced repressive modifications in iron-sufficient rats.
Conclusions:
- Early-life ID causes long-term BDNF dysregulation through an iron-dependent epigenetic mechanism involving JARID1B.
- Choline supplementation employs a distinct mechanism to affect neural gene regulation, with potential negative epigenetic consequences in iron-sufficient conditions.
- Further research is needed on choline's epigenetic effects before its use as an adjunctive therapy.
Abstract:
Early-life iron deficiency (ID) causes long-term neurocognitive impairments and gene dysregulation that can be partially mitigated by prenatal choline supplementation. The long-term gene dysregulation is hypothesized to underlie cognitive dysfunction. However, mechanisms by which iron and choline mediate long-term gene dysregulation remain unknown. In the present study, using a well-established rat model of fetal-neonatal ID, we demonstrated that ID downregulated hippocampal expression of the gene encoding JmjC-ARID domain-containing protein 1B (JARID1B), an iron-dependent histone H3K4 demethylase, associated with a higher histone deacetylase 1 (HDAC1) enrichment and a lower enrichment of acetylated histone H3K9 (H3K9ac) and phosphorylated cAMP response element-binding protein (pCREB). Likewise, ID reduced transcriptional capacity of the gene encoding brain-derived neurotrophic factor (BDNF), a target of JARID1B, associated with repressive histone modifications such as lower H3K9ac and pCREB enrichments at the Bdnf promoters in the adult rat hippocampus. Prenatal choline supplementation did not prevent the ID-induced chromatin modifications at these loci but induced long-lasting repressive chromatin modifications in the iron-sufficient adult rats. Collectively, these findings demonstrated that the iron-dependent epigenetic mechanism mediated by JARID1B accounted for long-term Bdnf dysregulation by early-life ID. Choline supplementation utilized a separate mechanism to rescue the effect of ID on neural gene regulation. The negative epigenetic effects of choline supplementation in the iron-sufficient rat hippocampus necessitate additional investigations prior to its use as an adjunctive therapeutic agent.
