Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans

Abstract

The aim of this study was to investigate the dynamics and relationship between DNA methylation and gene expression during early T-cell development. Mononuclear cells were collected at birth and at 12 months from 60 infants and were either activated with anti-CD3 for 24 h or cultured in media alone, and the CD4 þ T-cell subset purified. DNA and RNA were co-harvested and DNA methylation was measured in 450 000 CpG sites in parallel with expression measurements taken from 25 000 genes. In unstimulated cells, we found that a subset of 1188 differentially methylated loci were associated with a change in expression in 599 genes (adjusted P valueo0.01, b-fold 40.1). These genes were enriched in reprogramming regions of the genome known to control pluripotency. In contrast, over 630 genes were induced following low-level T-cell activation, but this was not associated with any significant change in DNA methylation. We conclude that DNA methylation is dynamic during early T-cell development, and has a role in the consolidation of T-cell-specific gene expression. During the early phase of clonal expansion, DNA methylation is stable and therefore appears to be of limited importance in short-term T-cell responsiveness.

Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy

“…These age-related variations in the CD4+ T-cell epigenome have previously been reported and were not the focus of the current analysis. 5 A more thorough examination of other sources of variation suggested consistent differences between phenotypes, which appear driven by only a minor proportion of probes on the array (5022 probes by ANOVA, P < 0.01, Fig. 1B).…”

“…3 DNA methylation is a widely studied epigenetic modification, tightly regulated during hematopoietic development. 4,5 Studies show that environmental exposures, such as dietary factors 6,7 and air pollution, 8 as well as stochastic factors can alter DNA methylation profiles in blood. Thus, variation in the DNA methylation profile during immune development could stably alter the host immune response at the individual level, or may underscore much of the variation in the clinical manifestations of allergic diseases at the population level.…”

Epigenetic editing: How cutting-edge targeted epigenetic modification might provide novel avenues for autoimmune disease therapy

“…It comes as no surprise, given the requirement for long-lasting gene transcription control during differentiation, that epigenetic mechanisms are at the heart of regulating these transcription factors, as well as the subsequent transcriptional programs that define immune cell subsets. Indeed, even nuanced cellular subsets can be robustly identified by differences in epigenetic patterns [68] which may be used to define the appropriate subset to which an unknown cell type belongs based on epigenetic data alone [69]. In fact, the ability to estimate the composition of a mixed whole blood sample based on genome-wide DNA methylation data is a feature built in to many modern epigenetics statistical analysis software pipelines [70].…”

Lactobacillus reuteri, Infant Allergy Prevention and Childhood Immune Maturation

“…Possibly, hypermethylation of the IFNG promoter may restrict expression of the IFNG gene. A permissive epigenetic state at the IL13 locus has been described for human naive neonatal CD4 cells as consistent with the Th2 skewing of the immune system early in life [96,97]. Prenatal environmental exposures may also alter gene expression via epigenetic mechanisms, aiming to induce physiological adaptations to the anticipated postnatal environment, but potentially also increasing disease susceptibility in the offspring [98].…”