The transcription factor E2A activates multiple enhancers that drive Rag expression in developing T and B cells

• Published in: Science immunology Vol. 5; no. 51
• Main Authors: Miyazaki, Kazuko, Watanabe, Hitomi, Yoshikawa, Genki, Chen, Kenian, Hidaka, Reiko, Aitani, Yuki, Osawa, Kai, Takeda, Rie, Ochi, Yotaro, Tani-Ichi, Shizue, Uehata, Takuya, Takeuchi, Osamu, Ikuta, Koichi, Ogawa, Seishi, Kondoh, Gen, Lin, Yin C, Ogata, Hiroyuki, Miyazaki, Masaki
• Format: Journal Article
• Language: English
• Published: United States 04.09.2020
• Subjects: Animals; Animals, Genetically Modified; B-Lymphocytes - immunology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - immunology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; Female; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Male; Mice; T-Lymphocytes - immunology
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.abb1455

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 ( ) and immunoglobulin ( ) genes. Although and expression is largely restricted to adaptive lymphoid lineage cells, it remains unclear how gene expression is regulated in a cell lineage-specific manner. Here, we identified three distinct cis-regulatory elements, a T cell lineage-specific enhancer ( ) and the two B cell-specific elements, and By generating mice lacking either or and , we demonstrate that these distinct sets of regulatory elements drive the expression of 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 , we demonstrate that recruitment of E2A to this site is essential for orchestrating changes in chromatin conformation that drive expression of genes in T cells. By mapping cis-regulatory elements and generating multiple mouse strains lacking distinct enhancer elements, we demonstrate expression of genes in developing T and B cells to be driven by distinct sets of E2A-dependent cis-regulatory modules.