The intranuclear position of many genes has been correlated with their activity state, suggesting that migration to functional subcompartments may influence gene expression. Indeed, nascent RNA production and RNA polymerase II seem to be localized into discrete foci or 'transcription factories'. Current estimates from cultured cells indicate that multiple genes could occupy the same factory, although this has not yet been observed. Here we show that, during transcription in vivo, distal genes colocalize to the same transcription factory at high frequencies. Active genes are dynamically organized into shared nuclear subcompartments, and movement into or out of these factories results in activation or abatement of transcription. Thus, rather than recruiting and assembling transcription complexes, active genes migrate to preassembled transcription sites.The activity state of a gene can often be correlated with its intranuclear localization to specific subregions or its position relative to constitutive heterochromatin [1][2][3][4][5][6] ; however, it is unclear whether activation or repression of an individual gene is a cause or consequence of intranuclear position. Transcriptionally active genes have been proposed to associate with transcription factories, discrete nuclear sites of nascent RNA production and concentrated transcriptional components, such as RNA polymerase [7][8][9][10][11][12] . Calculations using the number of RNA polymerase II (RNAP II) transcription factories in HeLa cells (several thousand per nucleus) and estimates of the number of transcription units suggest that several active genes could occupy the same factory 10

The discovery of interchromosomal interactions in higher eukaryotes points to a functional interplay between genome architecture and gene expression, challenging the view of transcription as a one-dimensional process. However, the extent of interchromosomal interactions and the underlying mechanisms are unknown. Here we present the first genome-wide analysis of transcriptional interactions using the mouse globin genes in erythroid tissues. Our results show that the active globin genes associate with hundreds of other transcribed genes, revealing extensive and preferential intra- and interchromosomal transcription interactomes. We show that the transcription factor Klf1 mediates preferential co-associations of Klf1-regulated genes at a limited number of specialized transcription factories. Our results establish a new gene expression paradigm, implying that active co-regulated genes and their regulatory factors cooperate to create specialized nuclear hot spots optimized for efficient and coordinated transcriptional control.