Activation of Mouse : Uncoupling RUNX1 Function from Its Cooperative Binding with ETS1.

T lineage commitment requires the coordination of key transcription factors (TFs) in multipotent progenitors that transition them away from other lineages and cement T cell identity. Two important TFs for the multipotent progenitors to T lineage transition are RUNX1 and ETS1, which bind cooperatively to composite sites throughout the genome, especially in regulatory elements for genes involved in T lymphopoiesis. Activation of the TCR β () locus in committed thymocytes is a critical process for continued development of these cells, and is mediated by an enhancer, Eβ, which harbors two RUNX-ETS composite sites.

Functional intersection of ATM and DNA-dependent protein kinase catalytic subunit in coding end joining during V(D)J recombination.

V(D)J recombination is initiated by the RAG endonuclease, which introduces DNA double-strand breaks (DSBs) at the border between two recombining gene segments, generating two hairpin-sealed coding ends and two blunt signal ends. ATM and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are serine-threonine kinases that orchestrate the cellular responses to DNA DSBs. During V(D)J recombination, ATM and DNA-PKcs have unique functions in the repair of coding DNA ends.

Regulation of antigen receptor gene assembly by genetic-epigenetic crosstalk.

Many aspects of gene function are coordinated by changes in the epigenome, which include dynamic revisions of chromatin modifications, genome packaging, subnuclear localization, and chromosome conformation. All of these mechanisms are used by developing lymphocytes to regulate the assembly of functional antigen receptor genes by V(D)J recombination. This somatic rearrangement of the genome must be tightly regulated to ensure proper B and T cell development and to avoid chromosomal translocations that cause lymphoid tumors.

Transcription-dependent mobilization of nucleosomes at accessible TCR gene segments in vivo.

Accessibility of chromosomal recombination signal sequences to the RAG protein complex is known to be essential for V(D)J recombination at Ag receptor loci in vivo. Previous studies have addressed the roles of cis-acting regulatory elements and germline transcription in the covalent modification of nucleosomes at Ag receptor loci. However, a detailed picture of nucleosome organization at accessible and inaccessible recombination signal sequences has been lacking.

Cutting edge: SWI/SNF mediates antisense Igh transcription and locus-wide accessibility in B cell precursors.

The stepwise process of Ag receptor gene assembly, termed V(D)J recombination, is coordinated during lymphocyte development by sweeping changes in chromatin that permit or deny access to a single recombinase enzyme. We now show that switching/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes are recruited to the Igh locus by an enhancer-dependent process and that these complexes are essential for generating recombinase accessibility throughout the locus. Depletion of SWI/SNF in pro-B cells also inhibits antisense transcription through all clusters of Igh gene segments, a pioneering process that has been implicated in the initial opening of chromatin.

Targeting V(D)J recombinase: putting a PHD to work.

In this issue of Immunity, Liu et al. (2007) show that V(D)J recombinase binds chromatin marked by H3K4 trimethylation. Because this mark associates with active promoters, the finding forges a new link between transcription, epigenetics, and recombinase targeting during lymphocyte development.

Essential function for SWI-SNF chromatin-remodeling complexes in the promoter-directed assembly of Tcrb genes.

The assembly of genes encoding antigen receptors is regulated by developmental changes in chromatin that either permit or deny access to a single variable-(diversity)-joining recombinase. These changes are guided by transcriptional promoters and enhancers, which serve as accessibility-control elements in antigen-receptor loci. The function of each accessibility-control element and the factors they recruit to remodel chromatin remain obscure.

Accessibility control of V(D)J recombination.

Mammals contend with a universe of evolving pathogens by generating an enormous diversity of antigen receptors during lymphocyte development. Precursor B and T cells assemble functional immunoglobulin (Ig) and T cell receptor (TCR) genes via recombination of numerous variable (V), diversity (D), and joining (J) gene segments. Although this combinatorial process generates significant diversity, genetic reorganization is inherently dangerous.

Targeted inhibition of V(D)J recombination by a histone methyltransferase.

The tissue- and stage-specific assembly of antigen receptor genes by V(D)J recombination is regulated by changes in the chromatin accessibility of target gene segments. This dynamic remodeling process is coordinated by cis-acting promoters and enhancers, which function as accessibility control elements. The basic epigenetic mechanisms that activate or repress chromatin accessibility to V(D)J recombinase remain unclear.