YY1 helps to bring loose ends together.

Ubiquitously expressed transcription factor Yin Yang 1 (YY1) has long been believed to play some role in immunoglobulin gene regulation, because it associates with multiple Ig enhancer elements including the heavychain intron and 3 enhancers as well as the Ig 3 enhancer (Park and Atchison 1991; Gordon et al. 2003). Early on, YY1 was noted to have bifunctional properties, in that it could either repress or activate transcription, depending on binding site context, protein interactions, or levels within the cell (Park and Atchison 1991; Seto et al. 1991; Shi et al. 1991; Lee et al. 1994, 1995; Bushmeyer et al. 1995). Numerous mechanisms of YY1 transcriptional control were observed and a number of activation/ repression models were proposed (Galvin and Shi 1997). YY1 function in transcription at the Ig loci was enigmatic, however, because no evidence exists for differential expression of YY1 during B-cell development, and deletion of enhancer YY1-binding sites had a marginal impact on enhancer activity as measured by transient expression assays (Park and Atchison 1991). It was generally assumed that YY1 might control some aspect of chromatin structure at the Ig loci not completely recapitulated by transient expression assays. Over the 16 years since its discovery, a very large number of genes regulated by YY1 were identified (Shrivastava and Calame 1994; Thomas and Seto 1999; Gordon et al. 2006). In addition, YY1 was observed to interact with a large number of proteins including coactivators, corepressors, and other transcription factors (Thomas and Seto 1999; Gordon et al. 2006). More recently, YY1 was implicated in cell cycle control, oncogenesis, imprinting control, X-chromosome inactivation, and Polycomb Group (PcG) function (Sui et al. 2004; Gordon et al. 2006; Kim et al. 2006, 2007; Donohoe et al. 2007). The huge numbers of processes believed to require YY1 function suggested that the protein would be crucial for development. Indeed, knockout of the gene results in peri-implantation lethality confirming its crucial function (Donohoe et al. 1999), but the role in B-cell development could only be revealed by the conditional knockout (CKO) approach that is used by Shi and colleagues (Liu et al. 2007) in this issue of Genes & Development. Shi and colleagues (Liu et al. 2007) created CKO mice lacking the gene for YY1 in B lymphocyte progenitors and observed a block in pro-B to pre-B-cell development. They found that pro-B cells lacking YY1 have normal DH-JH recombination but reduced frequency of VH-DHJH recombination, with the defect being most severe for more DH-distal VH genes. They further showed that pro-B cells lacking YY1 are defective in Ig heavy-chain (IgH) locus contraction, defined by close juxtaposition in nuclear chromatin of V and C gene segments separated from one another in the genome by large distances. Ig locus contraction has been observed previously by fluorescence in situ hybridization (FISH) in B cells undergoing V(D)J recombination (Kosak et al. 2002) and has been suggested to be mechanistically important for recombination of distal V regions. Importantly, introduction of a rearranged heavy-chain gene only partially complemented the YY1 CKO phenotype, suggesting additional roles for YY1 in early B-cell development. YY1 thus becomes the second transcription factor shown to be required for IgH locus contraction and VH-DHJH rearrangement. Significantly, the results of Shi et al. (Liu et al. 2007) show that YY1 does not affect expression of Pax5, the other transcription factor known to be required for locus contraction, VH-DHJH recombination, and B-cell commitment (Nutt et al. 1999; Fuxa et al. 2004). Furthermore, because faulty IgH locus contraction was the only defect related to VH-DHJH recombination observed by Shi et al. (Liu et al. 2007) in the YY1 CKO pro-B cells, these data provide new support for the idea that locus contraction may, in fact, be required for VH-DHJH recombination. This is particularly important because the role of locus contraction in VH-DHJH recombination, as well as mechanisms regulating and mediating IgH locus contraction, remain poorly understood. The data from Shi and colleagues (Liu et al. 2007) also help to bring together some concepts that have been at “loose ends” for understanding regulation of VH-DHJH recombination. These include the roles of the core IgH intronic enhancer (iEμ), the transcription of unrearranged IgH gene segments, and the alteration of chromatin structure in the IgH locus for locus contraction. Below, we review current understanding of the requirements for VH-DHJH recombination in the context of the Shi paper (Liu et al. 2007) and discuss how YY1 may act in this process. Corresponding author. E-MAIL klc1@columbia.edu; FAX (212) 305-1468. Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1559007.