Folate depletion alters DNA methylation in tissues relevant for childhood leukaemia

Epidemiological evidence suggests maternal folate status influences childhood leukaemia risk; however, the underlying mechanisms are unclear. Genetic aberrations, are considered leukaemia-initiating events, however, alone they are not sufficient for disease, with additional ‘hits’ required. Epigenetic alteration, i.e. DNA methylation, is one mechanism by which maternal folate is likely to contribute to disease. We investigated the relationship between folate depletion and DNA methylation in murine tissues relating to childhood leukaemia.

Female mice were allocated low or normal folate diets for 4 weeks before mating and onwards. Offspring were sampled at 17.5 days gestation and weaning. DNA was isolated from fetal livers and bone marrow of weaned mice. Tissues correspond to specific sites of haematopoiesis throughout the lifecycle relevant to leukaemic blasts. Epigenome-wide DNA methylation was profiled using Infinium® MouseMethylation BeadChips. R/Bioconductor packages identified differentially methylated points (DMP) and regions (DMRs). Pathway analysis was conducted by DAVID.

There were 598 DMPs (382 hypermethylated/216 hypomethylated) and 363 DMRs with significantly (FDR) altered methylation in response to folate depletion in the fetal liver. In bone marrow, 1206 DMPs (334 hypermethylated/852 hypomethylated) and 565 DMRs had significantly altered methylation in response to folate depletion. Only 3 DMPs and 13 DMRs were altered in both tissue types, suggesting highly tissue specific responses. Pathway analysis suggested 15 and 44 pathways could be altered in response to folate depletion in liver and bone marrow respectively, with 8 overlapping between tissues.

Whilst loci specific altered methylation appears to be different between tissues, the impact on biological pathways is similar.