Myc Dynamically and Preferentially Relocates to a Transcription Factory Occupied by Igh

Abstract

Transcription in mammalian nuclei is highly compartmentalized in RNA polymerase II-enriched nuclear foci known as transcription factories. Genes in cis and trans can share the same factory, suggesting that genes migrate to preassembled transcription sites. We used fluorescent in situ hybridization to investigate the dynamics of gene association with transcription factories during immediate early (IE) gene induction in mouse B lymphocytes. Here, we show that induction involves rapid gene relocation to transcription factories. Importantly, we find that the Myc proto-oncogene on Chromosome 15 is preferentially recruited to the same transcription factory as the highly transcribed Igh gene located on Chromosome 12. Myc and Igh are the most frequent translocation partners in plasmacytoma and Burkitt lymphoma. Our results show that transcriptional activation of IE genes involves rapid relocation to preassembled transcription factories. Furthermore, the data imply a direct link between the nonrandom interchromosomal organization of transcribed genes at transcription factories and the incidence of specific chromosomal translocations.

Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma

“…Intriguingly, in all ALCL cell lines lacking t(2;5), these gene pairs were in spatial proximity in a significant fraction of cells (10.6-22.5%; DL-40 cells were not included in this analysis due to the increased copy numbers of all of the various genes to 4-6 copies in this cell line). These values are in line with proximity frequencies observed between other translocation partners and nonrandomly paired genes (12,24). As a further control, NPM1 (5q35) and ALK (2p23) were not found in proximity to ZO-1 (15q13), which is not a translocation partner.…”

“…A paradigm for such transcription-mediated clustering of active genes comes from yeast, where tRNA genes cluster near the nucleolus, and actively transcribed tRNA genes exhibit higher recombination frequencies compared with inactive ones (38). In mammalian cells, transcription leads to physical association of the known translocation partners myc and IgH with each other (24,37). This interpretation is in line with the fact that transcription factor AP-1 is involved in the regulation of several genes that are deregulated in ALCL, namely Fra2 and JunB itself, Id2, and CSF1R (18,20,39).…”

Dynamics and interplay of nuclear architecture, genome organization, and gene expression

“…Genes that are capable of high expression levels, such as ␤-globin, ␣-globin, and immunoglobulin genes, seem to be constantly associated with "transcription factories" in cells that express these genes, whereas temporarily quiescent alleles are located away from the factories (Osborne et al 2004). Transcriptional activation of highly expressed genes such as immediate early genes involves their relocalization to preassembled transcription sites (Osborne et al 2007). These transcription sites may be maintained by flanking, ubiquitously expressed housekeeping genes (Zhou et al 2006), or by locus control regions (Ragoczy et al 2006).…”

The role of nuclear organization in cancer

“…There are several lines of evidence that transcriptional activity is important in the generation of recurrent translocations. In B lymphocytes, MYC and IGH frequently occupy the same transcription factory, thus leading to their close juxtaposition and facilitating recombination after the formation of DSBs [49]. In the study mentioned above from which the interchromosomal network model was derived, the amount of interchromosome intermingling correlated with both transcriptional activity and the frequency of translocations between the chromosomes [24].…”