Corrected and Republished from: BCL11A Is a Critical Component of a Transcriptional Network That Activates RAG Expression and V(D)J Recombination

Abstract

Recombination activating gene 1 (RAG1) and RAG2 are critical enzymes for initiating variable-diversity-joining [V(D)J] segment recombination, an essential process for antigen receptor expression and lymphocyte development. The BCL11A transcription factor is required for B cell and plasmacytoid dendritic cell (pDC) development, but its molecular function(s) in early B cell fate specification and commitment is unknown. We show here that the major B cell isoform, BCL11A-XL, binds directly to the RAG1 promoter as well as directly to regulatory regions of transcription factors previously implicated in both B cell and pDC development to activate RAG1 and RAG2 gene transcription in pro-and pre-B cells. We employed BCL11A overexpression with recombination substrates to demonstrate direct consequences of BCL11A/RAG modulation on V(D)J recombination. We conclude that BCL11A is a critical component of a transcriptional network that regulates B cell fate by controlling V(D)J recombination.KEYWORDS B cell development, Bcl11a, immunology, RAG, V(D)J R ecombination activating gene (RAG) endonuclease catalyzes the cleavage phase of V(D)J recombination (1-4). RAG is encoded by two adjacent genes, RAG1 and RAG2, whose products must interact to form an active endonuclease (5). Both RAG1 and RAG2 are essential for subsequent B and T lymphocyte development (4, 6). In cell-free systems, RAG1 and RAG2 are sufficient to cleave recombination substrates (7,8), but in vivo a number of additional factors are required for chromatin accessibility of V(D)J segments and for appropriate completion of the V(D)J joints (1-3).RAG expression occurs at two distinct points during B cell development. The first phase results in the assembly of the immunoglobulin heavy chain (IgH) in pro-B cells, whereas the second catalyzes Ig light chain (L) assembly in pre-B cells. RAG expression is tightly regulated at both the posttranscriptional and transcriptional levels (2). In addition to the individual promoters for RAG1 and RAG2, the RAG locus contains at least

Integrated Cross-Species Analysis Identifies a Conserved Transitional Dendritic Cell Population

“…Similar developmental associations can be implied by the expression of PTCRA-EGFP in pDCs and tDCs. These lymphoid characteristics may result from their shared expression of Bcl11a, which controls RAG-1 expression (Lee et al, 2017). Alternatively, they may be a consequence of an ectopic lymphoid program activated by TCF4, as previously suggested (Reizis, 2019).…”

Hierarchical assembly and disassembly of a transcriptionally active RAG locus in CD4+CD8+ thymocytes

“…In B cells, the RAG promoters are controlled by proximal, distal, and Erag enhancers distributed upstream of Rag2 (Monroe et al, 1999; Hsu et al, 2003). Studies of the Erag enhancer have revealed FOXO1 as a positive regulator of RAG expression and Gfi1b, Ebf1, and c-Myb as negative regulators (Amin and Schlissel, 2008; Schulz et al, 2012; Timblin and Schlissel, 2013; Lee et al, 2017; Timblin et al, 2017). RAG expression in T cells is controlled by distinct cis-regulatory elements.…”

A Newly Generated DOCK8-expressing T Follicular Helper Cell Type, aiCD4 T Cell, Causes Systemic Lupus Erythematosus: Self-Organized Criticality Theory

“…3e). PU.1 (Spi.1), which is normally undetectable in mature T cells, was also expressed, and the genes up-regulated by PU.1 such as Bcl11a, Lmo2, Mef2c, Syk, Lyn and Cd300a, but not Bcl11b, were up-regulated (54,56,57) (Fig. 3e).…”