Maternal Red Blood Cell Folate and Infant Vitamin B<sub>12</sub> Status Influence Methylation of Genes Associated with Childhood Acute Lymphoblastic Leukemia

Potter, Catherine; Moorman, Anthony V.; Relton, Caroline L; Ford, Dianne; Mathers, John C.; Strathdee, Gordon; McKay, Jill A.

doi:10.1002/mnfr.201800411

Cited by 12 publications

(5 citation statements)

References 47 publications

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“…Investigating DNA methylation changes in response to environmental risk factors seems to be an appealing method for studying the contribution and mechanism of action of these factors in promoting disease development (59). Using epigenetic biomarkers for maternal smoking during pregnancy, i.e., DNA methylation at AHRR and a recently established polyepigenetic smoking score, two recent studies provided evidence that prenatal tobacco smoke exposure was associated with a higher frequency of somatic gene deletions among childhood B-ALL cases (60,61).…”

Section: Epigeneticsmentioning

confidence: 99%

Risk Factors for Childhood Leukemia: Radiation and Beyond

Schmidt

Hornhardt

Erdmann

et al. 2021

Front. Public Health

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Childhood leukemia (CL) is undoubtedly caused by a multifactorial process with genetic as well as environmental factors playing a role. But in spite of several efforts in a variety of scientific fields, the causes of the disease and the interplay of possible risk factors are still poorly understood. To push forward the research on the causes of CL, the German Federal Office for Radiation Protection has been organizing recurring international workshops since 2008 every two to three years. In November 2019 the 6th International Workshop on the Causes of CL was held in Freising and brought together experts from diverse disciplines. The workshop was divided into two main parts focusing on genetic and environmental risk factors, respectively. Two additional special sessions addressed the influence of natural background radiation on the risk of CL and the progress in the development of mouse models used for experimental studies on acute lymphoblastic leukemia, the most common form of leukemia worldwide. The workshop presentations highlighted the role of infections as environmental risk factor for CL, specifically for acute lymphoblastic leukemia. Major support comes from two mouse models, the Pax5+/− and Sca1-ETV6-RUNX1 mouse model, one of the major achievements made in the last years. Mice of both predisposed models only develop leukemia when exposed to common infections. These results emphasize the impact of gene-environment-interactions on the development of CL and warrant further investigation of such interactions — especially because genetic predisposition is detected with increasing frequency in CL. This article summarizes the workshop presentations and discusses the results in the context of the international literature.

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Section: Epigeneticsmentioning

confidence: 99%

Risk Factors for Childhood Leukemia: Radiation and Beyond

Schmidt

Hornhardt

Erdmann

et al. 2021

Front. Public Health

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“…Beside these, others TFs were found to be associated with various signaling pathways which directly or indirectly modulates the cell growth, proliferation and apoptosis. For example, ASCL2 , which is hypermethylated in lymphocytic leukemias and SOX15 , a tumor suppressor, both act via WNT signaling pathway to modulate cell proliferation and invasion ( 65 , 75 , 76 ). Transcription factors, STAT4 and IRF5 both were reported to be expressed abnormally low in leukemia ( 64 , 77 ).…”

Section: Resultsmentioning

confidence: 99%

LncRNA Hmrhl regulates expression of cancer related genes in chronic myelogenous leukemia through chromatin association

et al. 2021

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Long non-coding RNA has emerged as a key regulator of myriad gene functions. One such lncRNA mrhl, reported by our group, was found to have important role in spermatogenesis and embryonic development in mouse. Recently, its human homolog, Hmrhl was shown to have differential expression in several type of cancers. In the present study, we further characterize molecular features of Hmrhl and gain insight into its functional role in leukemia by gene silencing and transcriptome-based studies. Results indicate its high expression in CML patient samples as well as in K562 cell line. Silencing experiments suggest role of Hmrhl in cell proliferation, migration & invasion. RNA-seq and ChiRP-seq data analysis further revealed its association with important biological processes, including perturbed expression of crucial TFs and cancer-related genes. Among them ZIC1, PDGRFβ and TP53 were identified as regulatory targets, with high possibility of triplex formation by Hmrhl at their promoter site. Further, overexpression of PDGRFβ in Hmrhl silenced cells resulted in rescue effect of cancer associated cellular phenotypes. In addition, we also found TAL-1 to be a potential regulator of Hmrhl expression in K562 cells. Thus, we hypothesize that Hmrhl lncRNA may play a significant role in the pathobiology of CML.

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“…As such, we hypothesize that such epigenetic changes may be latent, and only manifest influencing health in later life in response to additional biological triggers as a result of ageing, or external factors such as environmental cues. While many studies have demonstrated the influence of maternal folate status alone during pregnancy on DNA methylation in the offspring, [24][25][26][27][28] to the best of our knowledge, none have used genome-wide analysis to investigate potentially persistent changes across the life course. Here, we utilized data from a mouse model to uncover eight genes that were modestly hypermethylated in both the fetal and adult liver in response to maternal folate depletion during pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…[9] Indeed, many studies have demonstrated that maternal folate intake during pregnancy influences the offspring methylome. [24][25][26][27][28] However, to the best of our knowledge, no study has used genome-wide assessment to investigate if observed changes in methylation as a result of maternal folate depletion alone during pregnancy are likely to persist from development into adulthood, and therefore with potential to influence later-life health.…”

Section: Introductionmentioning

confidence: 99%

Impact of In Utero Folate Exposure on DNA Methylation and Its Potential Relevance for Later‐Life Health—Evidence from Mouse Models Translated to Human Cohorts

Kok

Richmond²,

Adriaens

et al. 2021

Molecular Nutrition Food Res

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Scope: Persistent DNA methylation changes may mediate effects of early-life exposures on later-life health. Human lifespan is challenging for prospective studies, therefore data from longitudinal studies are limited. Projecting data from mouse models of early-life exposure to human studies offers a tool to address this challenge. Methods and Results: C57BL/6J mice were fed low/normal folate diets before and during pregnancy and lactation. Genome-wide promoter methylation was measured in male offspring livers at 17.5 days gestation and 28 weeks. Eight promoters were concurrently hypermethylated by folate depletion in fetuses and adults (>1.10 fold-change; p < 0.05). Processes/pathways potentially influenced by global changes, and function of these eight genes, suggest neurocognitive effects. Human observational and randomized controlled trial data were interrogated for translation. Methylation at birth was inversely associated with maternal plasma folate in six genes (−1.15% to −0.16% per nmol L −1 ; p < 0.05), while maternal folic acid supplementation was associated with differential methylation of four genes in adulthood. Three CpGs were persistently hypermethylated with lower maternal folate (p = 0.04). Conclusion: Some persistent folate-induced methylation changes in mice are mirrored in humans. This demonstrates utility of mouse data in identifying human loci for interrogation as biomarkers of later-life health.

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Maternal Red Blood Cell Folate and Infant Vitamin B₁₂ Status Influence Methylation of Genes Associated with Childhood Acute Lymphoblastic Leukemia

Abstract: Findings demonstrate proof of concept for a plausible mechanism, i.e., variation in DNA methylation, by which low intake of folate, and related B-vitamins during pregnancy may influence ALL risk.

Cited by 12 publications

References 47 publications

Risk Factors for Childhood Leukemia: Radiation and Beyond

Risk Factors for Childhood Leukemia: Radiation and Beyond

LncRNA Hmrhl regulates expression of cancer related genes in chronic myelogenous leukemia through chromatin association

Impact of In Utero Folate Exposure on DNA Methylation and Its Potential Relevance for Later‐Life Health—Evidence from Mouse Models Translated to Human Cohorts

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Maternal Red Blood Cell Folate and Infant Vitamin B12 Status Influence Methylation of Genes Associated with Childhood Acute Lymphoblastic Leukemia

Abstract: Findings demonstrate proof of concept for a plausible mechanism, i.e., variation in DNA methylation, by which low intake of folate, and related B-vitamins during pregnancy may influence ALL risk.

Cited by 12 publications

References 47 publications

Risk Factors for Childhood Leukemia: Radiation and Beyond

Risk Factors for Childhood Leukemia: Radiation and Beyond

LncRNA Hmrhl regulates expression of cancer related genes in chronic myelogenous leukemia through chromatin association

Impact of In Utero Folate Exposure on DNA Methylation and Its Potential Relevance for Later‐Life Health—Evidence from Mouse Models Translated to Human Cohorts

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Product

Resources

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Maternal Red Blood Cell Folate and Infant Vitamin B₁₂ Status Influence Methylation of Genes Associated with Childhood Acute Lymphoblastic Leukemia