Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampus
Abstract Background Iron deficiency (ID) during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive hippocampal gene dysregulation. Prenatal choline supplementation partially normalizes these effects, suggesting an interaction between iron and chol...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | BMC Genomics |
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| Online Access: | https://doi.org/10.1186/s12864-024-10230-4 |
| _version_ | 1827310398131404800 |
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| author | Shirelle X. Liu Aarthi Ramakrishnan Li Shen Jonathan C. Gewirtz Michael K. Georgieff Phu V. Tran |
| author_facet | Shirelle X. Liu Aarthi Ramakrishnan Li Shen Jonathan C. Gewirtz Michael K. Georgieff Phu V. Tran |
| author_sort | Shirelle X. Liu |
| collection | DOAJ |
| description | Abstract Background Iron deficiency (ID) during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive hippocampal gene dysregulation. Prenatal choline supplementation partially normalizes these effects, suggesting an interaction between iron and choline in hippocampal transcriptome regulation. To understand the regulatory mechanisms, we investigated epigenetic marks of genes with altered chromatin accessibility (ATAC-seq) or poised to be repressed (H3K9me3 ChIP-seq) in iron-repleted adult rats having experienced fetal-neonatal ID exposure with or without prenatal choline supplementation. Results Fetal-neonatal ID was induced by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Half of the pregnant dams were given supplemental choline (5.0 g/kg) from G11–18. This resulted in 4 groups at P65 (Iron-sufficient [IS], Formerly Iron-deficient [FID], IS with choline [ISch], and FID with choline [FIDch]). Hippocampi were collected from P65 iron-repleted male offspring and analyzed for chromatin accessibility and H3K9me3 enrichment. 22% and 24% of differentially transcribed genes in FID- and FIDch-groups, respectively, exhibited significant differences in chromatin accessibility, whereas 1.7% and 13% exhibited significant differences in H3K9me3 enrichment. These changes mapped onto gene networks regulating synaptic plasticity, neuroinflammation, and reward circuits. Motif analysis of differentially modified genomic sites revealed significantly stronger choline effects than early-life ID and identified multiple epigenetically modified transcription factor binding sites. Conclusions This study reveals genome-wide, stable epigenetic changes and epigenetically modifiable gene networks associated with specific chromatin marks in the hippocampus, and lays a foundation to further elucidate iron-dependent epigenetic mechanisms that underlie the long-term effects of fetal-neonatal ID, choline, and their interactions. |
| first_indexed | 2024-04-24T19:59:09Z |
| format | Article |
| id | doaj.art-511ec710533a4bcf895fd68df659afb4 |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-04-24T19:59:09Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-511ec710533a4bcf895fd68df659afb42024-03-24T12:11:17ZengBMCBMC Genomics1471-21642024-03-0125111710.1186/s12864-024-10230-4Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampusShirelle X. Liu0Aarthi Ramakrishnan1Li Shen2Jonathan C. Gewirtz3Michael K. Georgieff4Phu V. Tran5Department of Pediatrics, University of MinnesotaIcahn School of Medicine at Mount SinaiIcahn School of Medicine at Mount SinaiDepartment of Psychology, University of MinnesotaDepartment of Pediatrics, University of MinnesotaDepartment of Pediatrics, University of MinnesotaAbstract Background Iron deficiency (ID) during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive hippocampal gene dysregulation. Prenatal choline supplementation partially normalizes these effects, suggesting an interaction between iron and choline in hippocampal transcriptome regulation. To understand the regulatory mechanisms, we investigated epigenetic marks of genes with altered chromatin accessibility (ATAC-seq) or poised to be repressed (H3K9me3 ChIP-seq) in iron-repleted adult rats having experienced fetal-neonatal ID exposure with or without prenatal choline supplementation. Results Fetal-neonatal ID was induced by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Half of the pregnant dams were given supplemental choline (5.0 g/kg) from G11–18. This resulted in 4 groups at P65 (Iron-sufficient [IS], Formerly Iron-deficient [FID], IS with choline [ISch], and FID with choline [FIDch]). Hippocampi were collected from P65 iron-repleted male offspring and analyzed for chromatin accessibility and H3K9me3 enrichment. 22% and 24% of differentially transcribed genes in FID- and FIDch-groups, respectively, exhibited significant differences in chromatin accessibility, whereas 1.7% and 13% exhibited significant differences in H3K9me3 enrichment. These changes mapped onto gene networks regulating synaptic plasticity, neuroinflammation, and reward circuits. Motif analysis of differentially modified genomic sites revealed significantly stronger choline effects than early-life ID and identified multiple epigenetically modified transcription factor binding sites. Conclusions This study reveals genome-wide, stable epigenetic changes and epigenetically modifiable gene networks associated with specific chromatin marks in the hippocampus, and lays a foundation to further elucidate iron-dependent epigenetic mechanisms that underlie the long-term effects of fetal-neonatal ID, choline, and their interactions.https://doi.org/10.1186/s12864-024-10230-4Iron deficiencyCholineChromatin accessibilityH3K9me3 ChIP-seqHippocampusEpigenetics |
| spellingShingle | Shirelle X. Liu Aarthi Ramakrishnan Li Shen Jonathan C. Gewirtz Michael K. Georgieff Phu V. Tran Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampus BMC Genomics Iron deficiency Choline Chromatin accessibility H3K9me3 ChIP-seq Hippocampus Epigenetics |
| title | Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampus |
| title_full | Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampus |
| title_fullStr | Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampus |
| title_full_unstemmed | Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampus |
| title_short | Chromatin accessibility and H3K9me3 landscapes reveal long-term epigenetic effects of fetal-neonatal iron deficiency in rat hippocampus |
| title_sort | chromatin accessibility and h3k9me3 landscapes reveal long term epigenetic effects of fetal neonatal iron deficiency in rat hippocampus |
| topic | Iron deficiency Choline Chromatin accessibility H3K9me3 ChIP-seq Hippocampus Epigenetics |
| url | https://doi.org/10.1186/s12864-024-10230-4 |
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