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Recombination activating genes (RAGs) RAG1 and RAG2 play central roles in assembling functional T and B cell receptors in developing lymphocytes. Expression of Rag1 and Rag2 in hematopoiesis is restricted to these two lymphoid lineages, but precisely how this is accomplished has remained a mystery. Here, Miyazaki et al. have identified three key enhancer elements that recruit the transcription factor E2A to promote the expression of Rag1 and Rag2 genes during lymphocyte development. By generating mouse strains lacking one or more of these enhancer elements, they report that T and B cells use distinct enhancer modules to activate and maintain expression of Rag1 and Rag2 genes.
Abstract
Cell type–specific gene expression is driven by the interplay between lineage-specific transcription factors and cis-regulatory elements to which they bind. Adaptive immunity relies on RAG-mediated assembly of T cell receptor (TCR) and immunoglobulin (Ig) genes. Although Rag1 and Rag2 expression is largely restricted to adaptive lymphoid lineage cells, it remains unclear how Rag gene expression is regulated in a cell lineage–specific manner. Here, we identified three distinct cis-regulatory elements, a T cell lineage–specific enhancer (R-TEn) and the two B cell–specific elements, R1B and R2B. By generating mice lacking either R-TEn or R1B and R2B, we demonstrate that these distinct sets of regulatory elements drive the expression of Rag genes in developing T and B cells. What these elements have in common is their ability to bind the transcription factor E2A. By generating a mouse strain that carries a mutation within the E2A binding site of R-TEn, we demonstrate that recruitment of E2A to this site is essential for orchestrating changes in chromatin conformation that drive expression of Rag genes in T cells. By mapping cis-regulatory elements and generating multiple mouse strains lacking distinct enhancer elements, we demonstrate expression of Rag genes in developing T and B cells to be driven by distinct sets of E2A-dependent cis-regulatory modules.
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