The choice of the first paper presented in 2013 is important! So here it is :]
The fantastic talk that Shimon Sakaguchi gave, on regulatory T cells of course, at ECI in Glasgow (see meeting report here – 06/10/2012), is now available to everyone as publication in Immunity! This paper goes very well with my previous entry on “master transcription factors”. This work also suggests that master transcription factors, particularly Foxp3, are not directly coupled to chromatin remodeling. Here, this is studied through CpG DNA methylation (as a reminder: methylated DNA on CpG islands is repressed while demethylated DNA is prone to transcription).
Of course, cell differentiation is determined by both alteration of transcriptional cascade and epigenomic regulation.
Therefore, to fully understand the mechanisms of actions of the master transcription factors, and how they allow, or not, the plasticity of T helper / regulatory cells, we need to precisely dissect their role in epigenetic mechanisms (such as DNA methylation, histone modification), nucleosome positioning, microRNAs expression and merely induction of gene transcription.
The approach of Ohkura et al, was to analyse the level of DNA methylation and Foxp3 expression of naturally occurring Foxp3+CD25+CD4+ Treg (nTreg) cells.
They showed that DNA hypomethylation, that is associated with gene expression, targets specific genes, happens prior to and is uncoupled with Foxp3 expression.
• Surprisingly nTreg cells do not present a specific genome-wide landscape of DNA methylation.
• However, CpG hypomethylation of a selectively limited set of regions, which includes Foxp3 intron 1, Tnfrsf18 = Gitr exon 5, Ctla4 exon 2, and Ikzf4 = Eos intron 1b, is exclusively imprinted in nTreg cells compared with induced Treg cells.
• CpG hypomethylation profil of the limited Treg-genes occurs even in the absence of Foxp3 in Treg-like cells.
• CpG hypomethylation of the Treg cell-associated molecules is more accurately correlated with the nTreg cell lineage compared with:
— mRNA expression
— histone H3K4me3 modification
— protein expression
• The establishment of nTreg-Me is required for Foxp3+ T cells to acquire nTreg cell-type gene expression, full suppressive activity, and sustained expression of Treg cell function-associated molecules.
• TCR stimulation triggers nTreg-Me but additional factors are also required for establishing the complete demethylation profil.
In conclusion, I encourage again (!) anyone interested in T cell differentiation to read this intriguing paper “independent roles of Foxp3 expression and of epigenetic changes for Treg cell fate determination and functional stability”.