Silencing and Nuclear Repositioning of the λ5 Gene Locus at the Pre-B Cell Stage Requires Aiolos and OBF-1

The chromatin regulator Aiolos and the transcriptional coactivator OBF-1 have been implicated in regulating aspects of B cell maturation and activation. Mice lacking either of these factors have a largely normal early B cell development. However, when both factors are eliminated simultaneously a block is uncovered at the transition between pre-B and immature B cells, indicating that these proteins exert a critical function in developing B lymphocytes. In mice deficient for Aiolos and OBF-1, the numbers of immature B cells are reduced, small pre-BII cells are increased and a significant impairment in immunoglobulin light chain DNA rearrangement is observed. We identified genes whose expression is deregulated in the pre-B cell compartment of these mice. In particular, we found that components of the pre-BCR, such as the surrogate light chain genes λ5 and VpreB, fail to be efficiently silenced in double-mutant mice. Strikingly, developmentally regulated nuclear repositioning of the λ5 gene is impaired in pre-B cells lacking OBF-1 and Aiolos. These studies uncover a novel role for OBF-1 and Aiolos in controlling the transcription and nuclear organization of genes involved in pre-BCR function

Enhancer talk.

Enhancers are short noncoding segments of DNA (100-1000 bp) that control the temporal and spatial activity of genes in an orientation-independent manner. They can be separated from their target genes by large distances and are thus known as distal regulatory elements. One consequence of the variability in the distance separating enhancers and their target promoters is that it is difficult to determine which elements are involved in the regulation of a particular gene. Moreover, enhancers can be found in clusters in which multiple regulatory elements control expression of the same target gene. However, little is known about how the individual elements contribute to gene expression. Here, we describe how chromatin conformation promotes and constraints enhancer activity. Further, we discuss enhancer clusters and what is known about the contribution of individual elements to the regulation of target genes. Finally, we examine the reliability of different methods used to identify enhancers

Equal opportunity for all

EMBO J 31 7, 1666–1678 (2012); 02282012 By sequencing tens of millions of TCRα transcripts from naive mouse CD8(+) T cells, Genolet et al (2012) show that the TCRα repertoire is at least as diverse as the TCRβ repertoire. This overturns a long held view in the field that recombination of the Tcra locus occurs in a co-ordinate sequential bidirectional manner that relies on proximity of Vα and Jα gene segments. The observation that rearrangement of all possible Vα-Jα combinations can occur is consistent with an alternative model in which intralocus loop formation/locus contraction enables an opportunity for all Vα gene segments to recombine with Jα gene segments