Folic acid induces intake-related changes in the mammary tissue transcriptome of C57BL/6 mice
Folic acid induces intake-related changes in the mammary tissue transcriptome of C57BL/6 mice
Folic acid (FA) intake has been associated with increased breast cancer risk in some studies. Although underlying mechanisms are unknown, epigenetic modifications that persistently alter transcription have been suggested. We tested the hypothesis that high FA (HFA) intake alters the adult mammary transcriptome in a manner consistent with increased potential for carcinogenesis, detectable beyond the period of intake. C57BL/6 mice were fed control FA (CFA) (1 mg/kg diet) or HFA (5 mg/kg diet) diets for 4 weeks, followed by AIN93M maintenance diet for 4 weeks. Plasma 5-methyltetrahydrofolate, p-aminobenzoylglutamate and unmetabolised FA concentrations were greater (1.62, 1.56, 5.80-fold, respectively) in HFA compared to CFA mice. RNA sequencing of the mammary transcriptome (~20 million reads) showed 222 transcripts (191 upregulated) differentially expressed between groups. Gene Set Enrichment showed upregulated genes significantly enriched in Epithelial Mesenchymal Transition, Myogenesis and Apical Junction and downregulated genes in E2F targets, MYC targets and G2M checkpoint. Cancer was the most altered Disease and Disorder pathway, with Metastasis, Mammary Tumour and Growth of Tumour the most upregulated pathways. ChIP-seq enrichment analysis showed that targets of histone methyltransferase EZH2 were enriched in HFA mice. This study demonstrates HFA intake during adulthood induces mammary transcriptome changes, consistent with greater tumorigenic potential.
breast cancer, EZH2, folic acid, mammary glands, transcriptome
1-13
Burton, Mark A
250319ad-90dc-4651-b118-d5dbe5eaafa6
Antoun, Elie
10fc5678-b33c-4410-977d-b11234031791
Penailillo, Reyna S
3ce3d685-cdc0-4409-9bb8-35ad1e1d1b62
Burdge, Graham C
09d60a07-8ca1-4351-9bf1-de6ffcfb2159
Lillycrop, Karen A
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
15 September 2020
Burton, Mark A
250319ad-90dc-4651-b118-d5dbe5eaafa6
Antoun, Elie
10fc5678-b33c-4410-977d-b11234031791
Penailillo, Reyna S
3ce3d685-cdc0-4409-9bb8-35ad1e1d1b62
Burdge, Graham C
09d60a07-8ca1-4351-9bf1-de6ffcfb2159
Lillycrop, Karen A
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Burton, Mark A, Antoun, Elie, Penailillo, Reyna S, Burdge, Graham C and Lillycrop, Karen A
(2020)
Folic acid induces intake-related changes in the mammary tissue transcriptome of C57BL/6 mice.
Nutrients, 12 (9), , [2821].
(doi:10.3390/nu12092821).
Abstract
Folic acid (FA) intake has been associated with increased breast cancer risk in some studies. Although underlying mechanisms are unknown, epigenetic modifications that persistently alter transcription have been suggested. We tested the hypothesis that high FA (HFA) intake alters the adult mammary transcriptome in a manner consistent with increased potential for carcinogenesis, detectable beyond the period of intake. C57BL/6 mice were fed control FA (CFA) (1 mg/kg diet) or HFA (5 mg/kg diet) diets for 4 weeks, followed by AIN93M maintenance diet for 4 weeks. Plasma 5-methyltetrahydrofolate, p-aminobenzoylglutamate and unmetabolised FA concentrations were greater (1.62, 1.56, 5.80-fold, respectively) in HFA compared to CFA mice. RNA sequencing of the mammary transcriptome (~20 million reads) showed 222 transcripts (191 upregulated) differentially expressed between groups. Gene Set Enrichment showed upregulated genes significantly enriched in Epithelial Mesenchymal Transition, Myogenesis and Apical Junction and downregulated genes in E2F targets, MYC targets and G2M checkpoint. Cancer was the most altered Disease and Disorder pathway, with Metastasis, Mammary Tumour and Growth of Tumour the most upregulated pathways. ChIP-seq enrichment analysis showed that targets of histone methyltransferase EZH2 were enriched in HFA mice. This study demonstrates HFA intake during adulthood induces mammary transcriptome changes, consistent with greater tumorigenic potential.
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Accepted/In Press date: 11 September 2020
Published date: 15 September 2020
Additional Information:
Funding Information:
Funding: This research was funded by The World Cancer Research Fund (WCRF), grant number 2012/614.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords:
breast cancer, EZH2, folic acid, mammary glands, transcriptome
Identifiers
Local EPrints ID: 468019
URI: http://eprints.soton.ac.uk/id/eprint/468019
ISSN: 2072-6643
PURE UUID: bb062df8-b995-498c-94f2-d88699ccca7e
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Date deposited: 27 Jul 2022 17:06
Last modified: 11 Jul 2024 01:58
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Author:
Elie Antoun
Author:
Reyna S Penailillo
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