Project description:Global N4 cytosine methylation catalyzed by a novel DNA methyltransferase is important for transcriptional programming, sperm mobility, and post-fertilization in Marchantia
Project description:The diet consumed by fathers prior to procreation impacts metabolic phenotypes in their offspring, but the mechanisms underlying such intergenerational information transfer remain obscure. Here, we carried out extensive analysis of cytosine methylation patterns in murine sperm, generating whole genome methylation maps for 4 pools of sperm samples and for 12 individual sperm samples, as well as 61 genome-scale reduced-representation bisulfite sequencing (RRBS) methylation maps, using samples obtained from male mice consuming various diets. We found that epivariation, either stochastic or due to unknown demographic or environmental factors, was a far stronger contributor to the sperm methylome than was the diet consumed. Variation in cytosine methylation was particularly dramatic over tandem repeat families, including ribosomal DNA (rDNA) repeats, and rDNA methylation levels were heritable from one generation to the next. However, rDNA methylation was strongly correlated with genetic variation in rDNA copy number, and analysis of hundreds of sperm samples revealed no consistent effect of diet on rDNA copy number or methylation level in sperm, indicating that paternal diet exerts an rDNA methylation-independent effect on offspring gene expression. These results reveal loci of genetic and epigenetic lability in the mammalian genome, but strongly argue against a direct mechanistic role for sperm cytosine methylation in dietary reprogramming of offspring metabolism.
Project description:We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression. Bisulfite-converted DNA from 144 samples were analyzed with the Illumina GoldenGate Methylation Cancer Panel I array.
Project description:To understand a role of MpMET in maintenance of cytpsine methylation and transposon silencing, we obtained a genome wide profile of 5-methylated cytosine from the Mpmet mutant of a model liverwort, Marchantia polymorpha.
Project description:We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression.
Project description:Early life exposures are critical in fetal programming and may influence function and health in later life. Adequate maternal folate consumption during pregnancy is essential for healthy fetal development and long-term offspring health. The mechanisms underlying fetal programming are poorly understood, but are likely to involve gene regulation. Epigenetic marks, including DNA methylation, regulate gene expression and are modifiable by folate supply. We observed before transcriptional changes in fetal liver in response to maternal folate depletion and hypothesised that these changes are due to altered gene promoter methylation. Female C57BL/6J mice were fed diets containing 2âmg or 0.4âmg folic acid/kg for 4âweeks before mating and throughout pregnancy. At 17.5 day gestation, genome-wide gene expression and promoter methylation were measured by microarray analysis in male fetal livers.
