Article

Two Forms of Loops Generate the Chromatin Conformation of the Immunoglobulin Heavy-Chain Gene Locus

Gene Regulation Section, Laboratory of Molecular Biology and Immunology, National Institute on Aging, Baltimore, MD 21224, USA.
Cell (Impact Factor: 33.12). 10/2011; 147(2):332-43. DOI: 10.1016/j.cell.2011.08.049
Source: PubMed

ABSTRACT The immunoglobulin heavy-chain (IgH) gene locus undergoes radial repositioning within the nucleus and locus contraction in preparation for gene recombination. We demonstrate that IgH locus conformation involves two levels of chromosomal compaction. At the first level, the locus folds into several multilooped domains. One such domain at the 3' end of the locus requires an enhancer, Eμ; two other domains at the 5' end are Eμ independent. At the second level, these domains are brought into spatial proximity by Eμ-dependent interactions with specific sites within the V(H) region. Eμ is also required for radial repositioning of IgH alleles, indicating its essential role in large-scale chromosomal movements in developing lymphocytes. Our observations provide a comprehensive view of the conformation of IgH alleles in pro-B cells and the mechanisms by which it is established.

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    • "Current data suggest that the Ig loci are organized as loops into rosette-like structures separated by spacer DNA (Jhunjhunwala et al, 2008, 2009; Lucas et al, 2010; Guo et al, 2011a). A number of domains have been identified at the IgH locus that adopt various conformations during development (Jhunjhunwala et al, 2008, 2009; Lucas et al, 2010; Guo et al, 2011a). At the prepro-B cell stage, these rosette domains are in an extended conformation, but in pro-B cells the structure changes such that each V region domain is repositioned with all V H regions approximately equidistant to the D H and J H regions, thus affording roughly equal access for recombination (Jhunjhunwala et al, 2008; Lucas et al, 2010). "
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    • "Long-range chromatin interactions with three regulatory sequences in particular, the 3 regulatory region (3 RR), the Eμ-intronic enhancer and the recently discovered intergenic control region 1 (IGCR1), seem important for proper rearrangement of the IgH locus. These loops may facilitate the inclusion of distal Vgenes, thereby enhancing the diversity of choice in usage of coding V elements during V(D)J recombination (Degner et al., 2011; Guo et al., 2011a,b; Ribeiro de Almeida et al., 2011; Seitan et al., 2011). Additionally, CTCF and cohesin may regulate chromatin accessibility and transcription in sub-regions of the loci, thereby directing the recombination machinery. "
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