Project description:Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. We characterized several models in which biological age, assessed primarily through analysis of DNA methylation, undergoes reversible changes. Pregnancy is one such example.
Project description:The methylation data were measured from longitudinal blood samples to study the longitudinal change of methylation in association with age.
Project description:Mammary gland development and luminal differentiation occur largely postnatally during puberty and pregnancy. To explore the role of DNA methylation in luminal cell differentiation and pregnancy-induced changes, we determined the genome-wide DNA methylation and gene expression profiles of mammary epithelial stem, luminal progenitor, and mature luminal cells at different reproductive stages. We found that pregnancy had the most significant effects on stem cells, inducing a distinct epigenetic state that remained stable through life. Integrated analysis of gene expression, DNA methylation, and histone modification profiles revealed cell type and reproductive stage-specific changes in molecular signatures. We also identified p27 and TGFβ signaling as key regulators of luminal progenitor cell proliferation based on their expression patterns and by the use of explant cultures. Our results suggest relatively minor changes in DNA methylation during luminal cell differentiation as compared to the significant effects of pregnancy on mammary epithelial stem cells. Mammary glands were collected from mice treated with DNA methylation inhibitor 5-azacytidine (AzaC) and histone deacetylase inhibitor valproic acid (VPA) at non-pregnant and pregnant stages for RNA extraction and hybridization on Affymetrix microarrays.
Project description:Mammary gland development and luminal differentiation occur largely postnatally during puberty and pregnancy. To explore the role of DNA methylation in luminal cell differentiation and pregnancy-induced changes, we determined the genome-wide DNA methylation and gene expression profiles of mammary epithelial stem, luminal progenitor, and mature luminal cells at different reproductive stages. We found that pregnancy had the most significant effects on stem cells, inducing a distinct epigenetic state that remained stable through life. Integrated analysis of gene expression, DNA methylation, and histone modification profiles revealed cell type and reproductive stage-specific changes in molecular signatures. We also identified p27 and TGFβ signaling as key regulators of luminal progenitor cell proliferation based on their expression patterns and by the use of explant cultures. Our results suggest relatively minor changes in DNA methylation during luminal cell differentiation as compared to the significant effects of pregnancy on mammary epithelial stem cells.
Project description:Background: Early life epigenetic programming influences adult health outcomes. Moreover, DNA methylation levels have been found to change more rapidly during the first years of life. Our aim was the identification and characterization of the CpG sites that are modified with time during the first years of life. We hypothesize that these DNA methylation changes would lead to the detection of genes that might be epigenetically modulated by environmental factors during early childhood and which, if disturbed, might contribute to susceptibility to diseases later in life. Methods: The study of the DNA methylation pattern of 485577 CpG sites was performed on 30 blood samples from 15 subjects, collected both at birth and at 5 years old, using Illumina® Infinium 450 k array. To identify differentially methylated CpG (dmCpG) sites, the methylation status of each probe was examined using linear models and the Empirical Bayes Moderated t test implemented in the limma package of R/Bioconductor. Surogate variable analysis was used to account for batch effects. Results: DNA methylation levels significantly changed from birth to 5 years of age in 6641 CpG sites. Of these, 36.79 % were hypermethylated and were associated with genes related mainly to developmental ontology terms, while 63.21 % were hypomethylated probes and associated with genes related to immune function. Conclusions: Our results suggest that DNA methylation alterations with age during the first years of life might play a significant role in development and the regulation of leukocyte-specific functions. This supports the idea that blood leukocytes experience genome remodeling related to their interaction with environmental factors, underlining the importance of environmental exposures during the first years of life and suggesting that new strategies should be take into consideration for disease prevention. Longitudinal study including 15 samples