The Evolution of Rag Gene Enhancers and Transcription Factor E and Id Proteins in the Adaptive Immune System.

Adaptive immunity relies on the V(D)J DNA recombination of immunoglobulin () and T cell receptor () genes, which enables the recognition of highly diverse antigens and the elicitation of antigen-specific immune responses. This process is mediated by recombination-activating gene (Rag) 1 and Rag2 (Rag1/2), whose expression is strictly controlled in a cell type-specific manner; the expression of genes represents a hallmark of lymphoid lineage commitment. Although genes are known to be evolutionally conserved among jawed vertebrates, how genes are regulated by lineage-specific transcription factors (TFs) and how their regulatory system evolved among vertebrates have not been fully elucidated. Here, we reviewed the current body of knowledge concerning the cis-regulatory elements (CREs) of genes and the evolution of the basic helix-loop-helix TF E protein regulating gene CREs, as well as the evolution of the antagonist of this protein, the Id protein. This may help to understand how the adaptive immune system develops along with the evolution of responsible TFs and enhancers.