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

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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. Many different types of cancer result from gene translocations. Specifically, two different chromosomes can be joined that fuse growth control genes with powerful regulatory elements, leading to unrestricted control of cell growth. Translocation partner genes must physically encounter each other in the nucleus to undergo a translocation; how they find each other in the crowded nucleus is unknown. We showed previously that gene transcription occurs at a few hundred discrete nuclear sites called transcription factories. In the current study we investigated the effects of activation of the Myc proto-oncogene and examined its location with respect to transcription factories and its common translocation partner, the immunoglobulin heavy chain (Igh) gene. We found that switching on the Myc gene leads to its rapid relocation to a transcription factory. Surprisingly, we found that the activated Myc frequently chooses the same transcription factory as the highly transcribing Igh gene. This close juxtaposition of translocation partner genes at a shared transcription factory may provide the opportunity for a chromosomal translocation, and thus may be the first step in the genesis of several types of cancers.