The Polycomb protein RING1B enables estrogen-mediated gene expression by promoting enhancer-promoter interaction and R-loop formation.

Polycomb complexes have traditionally been prescribed roles as transcriptional repressors, though increasing evidence demonstrate they can also activate gene expression. However, the mechanisms underlying positive gene regulation mediated by Polycomb proteins are poorly understood. Here, we show that RING1B, a core component of Polycomb Repressive Complex 1, regulates enhancer-promoter interaction of the bona fide estrogen-activated GREB1 gene.

Poor quality Vβ recombination signal sequences stochastically enforce TCRβ allelic exclusion.

The monoallelic expression of antigen receptor (AgR) genes, called allelic exclusion, is fundamental for highly specific immune responses to pathogens. This cardinal feature of adaptive immunity is achieved by the assembly of a functional AgR gene on one allele, with subsequent feedback inhibition of V(D)J recombination on the other allele. A range of epigenetic mechanisms have been implicated in sequential recombination of AgR alleles; however, we now demonstrate that a genetic mechanism controls this process for Tcrb.

Genome Topology Control of Antigen Receptor Gene Assembly.

The past decade has increased our understanding of how genome topology controls RAG endonuclease-mediated assembly of lymphocyte AgR genes. New technologies have illuminated how the large IgH, Igκ, TCRα/δ, and TCRβ loci fold into compact structures that place their numerous V gene segments in similar three-dimensional proximity to their distal recombination center composed of RAG-bound (D)J gene segments. Many studies have shown that CTCF and cohesin protein-mediated chromosome looping have fundamental roles in lymphocyte lineage- and developmental stage-specific locus compaction as well as broad usage of V segments.

A Spontaneous RAG1 Nonsense Mutation Unveils Naturally Occurring N-Terminal Truncated RAG1 Isoforms.

The RAG1 and RAG2 proteins are essential for the assembly of Ag receptor genes in the process known as VDJ recombination, allowing for an immense diversity of lymphocyte Ag receptors. Congruent with their importance, RAG1 and RAG2 have been a focus of intense study for decades. To date, RAG1 has been studied as a single isoform; however, our identification of a spontaneous nonsense mutation in the 5' region of the mouse Rag1 gene lead us to discover N-truncated RAG1 isoforms made from internal translation initiation.

Two Successive Inversional Vβ Rearrangements on a Single Allele Can Contribute to the TCRβ Repertoire.

Mammalian TCRβ loci contain 30 Vβ gene segments upstream and in the same transcriptional orientation as two DJCβ clusters, and a downstream Vβ (TRBV31) in the opposite orientation. The textbook view is upstream Vβs rearrange only by deletion and TRBV31 rearranges only by inversion to create VβDJCβ genes. In this study, we show in mice that upstream Vβs recombine through inversion to the DJCβ2 cluster on alleles carrying a preassembled -DJCβ1 gene.