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Nucleolar tethering mediates pairing between the IgH and Myc loci.

ABSTRACT: Gene loci on different chromosomes can preferentially colocalize in the cell nucleus. However, many of the mechanisms mediating this spatial proximity remain to be elucidated. The IgH locus on Chromosome 12 and the Myc locus on Chromosome 15 are a well-studied model for gene colocalization in murine B cells, where the two loci are positioned in close proximity at a higher than expected frequency. These gene loci are also partners in the chromosomal translocation that causes murine plasmacytoma and Burkitt's lymphoma. Because both Chromosome 12 and Chromosome 15 carry nucleolar organizer regions (NORs) in the most commonly studied mouse strains, we hypothesized that NOR-mediated tethering of the IgH and Myc loci to shared nucleoli could serve as a mechanism to drive IgH:Myc colocalization. Using mouse strains that naturally carry nucleolar organizer regions (NORs) on different sets of chromosomes, we establish that IgH and Myc are positioned proximal to nucleoli in a NOR dependent manner and show that their joint association with nucleoli significantly increases the frequency of IgH and Myc pairing. Thus we demonstrate that simple nucleolar tethering can increase the colocalization frequency of genes on NOR-bearing chromosomes.

SUBMITTER: Strongin DE

PROVIDER: S-EPMC4164489 | biostudies-literature | 2014 Sep-Oct

REPOSITORIES: biostudies-literature

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Nucleolar tethering mediates pairing between the IgH and Myc loci.

Strongin Daniel E DE Groudine Mark M Politz Joan C Ritland JC

Nucleus (Austin, Tex.) 20140901 5

Gene loci on different chromosomes can preferentially colocalize in the cell nucleus. However, many of the mechanisms mediating this spatial proximity remain to be elucidated. The IgH locus on Chromosome 12 and the Myc locus on Chromosome 15 are a well-studied model for gene colocalization in murine B cells, where the two loci are positioned in close proximity at a higher than expected frequency. These gene loci are also partners in the chromosomal translocation that causes murine plasmacytoma a ...[more]

PMID: 25482199

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Project description:B-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (Cmu) exons, which are the first of several sets of C(H) exons ('C(H) genes') within a C(H) locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cmu and replaces it with a downstream C(H) gene. An intronic enhancer (iEmu) between the variable region exons and Cmu promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3' regulatory region (Igh3'RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes. Transgenic mice bearing iEmu or Igh3'RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression. However, in many B-cell lymphomas, Igh-c-myc translocations delete iEmu and place c-myc up to 200 kb upstream of the Igh3'RR. Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes.

Dataset Information

Nucleolar tethering mediates pairing between the IgH and Myc loci.

Publications

Nucleolar tethering mediates pairing between the IgH and Myc loci.

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