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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    ABSTRACT: Conditional knock-out (KO) of Polycomb Group (PcG) protein YY1 results in pro-B cell arrest and reduced immunoglobulin locus contraction needed for distal variable gene rearrangement. The mechanisms that control these crucial functions are unknown. We deleted the 25 amino-acid YY1 REPO domain necessary for YY1 PcG function, and used this mutant (YY1ΔREPO), to transduce bone marrow from YY1 conditional KO mice. While wild-type YY1 rescued B-cell development, YY1ΔREPO failed to rescue the B-cell lineage yielding reduced numbers of B lineage cells. Although the IgH rearrangement pattern was normal, there was a selective impact at the Igκ locus that showed a dramatic skewing of the expressed Igκ repertoire. We found that the REPO domain interacts with proteins from the condensin and cohesin complexes, and that YY1, EZH2 and condensin proteins co-localize at numerous sites across the Ig kappa locus. Knock-down of a condensin subunit protein or YY1 reduced rearrangement of Igκ Vκ genes suggesting a direct role for YY1-condensin complexes in Igκ locus structure and rearrangement.
    The EMBO Journal 03/2013; 32. DOI:10.1038/emboj.2013.66 · 10.75 Impact Factor
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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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    ABSTRACT: Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus. We will summarize topological studies performed on four model gene loci: the α- and β-globin gene loci, the antigen receptor loci, the imprinted H19-Igf2 locus and the Hox gene clusters. Collectively, these studies show that regulatory DNA sequences physically contact genes to control their transcription. Proteins set up the 3D configuration of the genome and we will discuss the roles of the key structural organizers CTCF and cohesin, the nuclear lamina and the transcription machinery. Finally, genes adopt non-random positions in the nuclear interior. We will review studies on gene positioning and propose that cell-specific genome conformations can juxtapose a regulatory sequence on one chromosome to a responsive gene on another chromosome to cause altered gene expression in subpopulations of cells.
    Frontiers in Genetics 10/2012; 3:217. DOI:10.3389/fgene.2012.00217
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    ABSTRACT: Epigenetic regulation, including DNA methylation, histone modifications, and chromosomal organization, is emerging as a new layer of transcriptional regulation in retinal development and maintenance. Guided by intrinsic transcription factors and extrinsic signaling molecules, epigenetic regulation can activate and/or repress the expression of specific sets of genes, therefore playing an important role in retinal cell fate specification and terminal differentiation during development as well as maintaining cell function and survival in adults. Here, we review the major findings that have linked these mechanisms to the development and maintenance of retinal structure and function, with a focus on ganglion cells and photoreceptors. The mechanisms of epigenetic regulation are highly complex and vary among different cell types. Understanding the basic principles of these mechanisms and their regulatory pathways may provide new insight into the pathogenesis of retinal diseases associated with transcription dysregulation, and new therapeutic strategies for treatment.
    Journal of ocular biology, diseases, and informatics 09/2011; 4(3):121-36. DOI:10.1007/s12177-012-9083-0
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