(A) Basic genetic architecture of mouse Igh (top) and Tcrb (bottom), not drawn to scale. Variable (V, blue), diversity (D, red), and joining (J, green) gene segments as well as constant region exons (black) are represented as rectangles of the indicated colors. The purple rectangles depict relative positions of the Eμ and Eβ enhancers. The lower panel shows a magnification of DβJβ clusters within Tcrb. Black triangles represent RSSs. (B) Model for stepwise activation of DβJβ clusters in pro-T cells. Panel (i) shows early stages of activation in DN thymocytes when only a subset of TFs binds to Eβ and PDβ1, activating the long-range ACE function of Eβ, which displays the enhancer-specific mark H3K4me1 (yellow triangles). Panel (ii) depicts the spread of partially open chromatin by Eβ as indicated by the H3/H4ac marks (orange circles), which permits additional TF binding at PDβ1. Panel (iii) shows PDβ1-Eβ holocomplex formation, which presumably allows interaction with additional factors, including SWI-SNF. In panel (iv) recruited SWI-SNF remodels neighboring Dβ1 chromatin, allowing Pol II-directed transcription and rendering the Dβ1-Jβ RSSs (black triangles) accessible to RAG-1/2 complexes. Germline transcription also deposits H3K4me3 marks (blue cups) near PDβ1, which stabilize local interactions with RAG2 via its PHD motif.