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Epigenome Consortium Research Teams Tackle Immune Response Epigenetics

NEW YORK (GenomeWeb) – New research is starting to untangle the complex epigenetic interactions behind immune cell development, lineage determination and differentiation, and immune response to potential threats.

As part of a collection of papers published by representatives from the International Human Epigenome Consortium (IHEC), several teams delved into the genomic, epigenomic, transcriptional, and functional features mediating adaptive immunity — the arm of the human immune system that's acquired through a lifetime-worth of exposures to new pathogens, mutated cells, and other potential dangers that aren't destroyed by innate immunity.

For one of these studies, German investigators reporting in the journal Immunity examined memory immune cell differentiation with the help of epigenome data for human CD4+ T memory cells. Using bisulfite sequencing, chromatin immunoprecipitation (ChIP) sequencing, RNA sequencing, and other methods, they profiled everything from DNA methylation and histone modifications to coding and non-coding expression and DNA accessibility patterns in differentiating CD4+ cells sorted by flow cytometry from blood samples for three to 10 healthy female donors.

Based on patterns in these and other T cells from the donors' blood and bone marrow, the authors of the study saw signs of sequential, linear differentiation in the memory T cells. "We observed a progressive and proliferation-associated global loss of DNA methylation in heterochromatic parts of the genome during [memory T cell] differentiation," they wrote, noting that the memory T cells in bone marrow had distinct epigenetic profiles compared with those circulating in blood.

In a study in Cell Reports, researchers from Mexico, France, and Spain focused on regulatory and expression features found in CD8+ T cells, a form of so-called cytotoxic T cell lymphocyte. They used ChIP-seq and RNA-seq to compare histone modification marks and gene expression profiles in CD8+ cells from cord blood for four full term healthy babies and from blood samples for four adults between the ages of 22 and 55.

That team reported that neonate versions of the CD8+ T cells appeared more similar to innate immune components, both in terms of their epigenetic marks and expression of genes related to T cell signaling and cytotoxic activity — findings that may provide a partial explanation for infants' higher susceptibility to infectious pathogens.

A team from Italy and the Netherlands took a look at transcriptional patterns in tumor-infiltrating lymphocytes for an Immunity study. Using RNA sequencing, that group examined transcription by tumor-infiltrating CD4+ T cells from non-small cell lung cancer, colorectal cancer, adjacent normal, and blood samples, comparing T-regulatory and T-helper cell patterns in up to three-dozen samples per cell type. The analysis pointed to T-regulatory signatures associated with immune checkpoint activity and poorer prognosis in the cancer cases.

"We found that tumor-infiltrating [regulatory T lymphocytes] were highly suppressive, up-regulated several immune checkpoints, and expressed on the cell surfaces specific signature molecules … which were not previously described on [regulatory T] cells," authors of that study wrote.

Meanwhile, related studies by researchers involved in the BLUEPRINT epigenome project, published in Cell yesterday, described variation in the human immune cells and other blood cell-related traits that were detected using genetic, epigenetic, and/or transcriptomic profiling on large numbers of individuals.

For example, a Sanger Institute-led team tested CD14+ monocytes, CD16+ neutrophils, and naïve CD4+ T cells in as many as 197 individuals, mapping quantitative trait loci and allele-specific regulatory effects in the varied immune cell types. Another international group investigated variation in red cell, white cell, and platelet-related features in almost 173,500 individuals, leading to blood-related variants that overlapped with those implicated in the risk of heart disease, rheumatoid arthritis, and other conditions.

For their part, researchers from the Babraham Institute and elsewhere compiled information on promoter-interacting regions in 17 primary hematopoietic cell types with the help of promotor capture Hi-C methods, uncovering overlap with expression quantitative trait loci and common disease risk variants. Our sister publication GenomeWeb Daily News has more on the study, here.

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