Schoenfelder S, Sexton T, Chakalova L, Cope NF, Horton A, Andrews S, Kurukuti S, Mitchell JA, Umlauf D, Dimitrova DS, Eskiw CH, Luo Y, Wei C-L, Ruan Y, Bieker JJ, Fraser P (2010)
Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells.
Nature Genetics 42 53-61
*These authors contributed equally to this work
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The cells in a mammalian body fulfill very different functions, yet the genetic information they contain is, with very few exceptions, identical. For example, a liver cell needs to perform functions that largely differ from those of a brain cell. The identity of a cell is defined by how it interprets its genetic information. This is mediated by a process called transcription, during which specific segments of the genetic information, the genes, are transcribed into RNA. RNAs then function as messengers carrying the instructions on how to produce specific proteins, the work-horses of the cell. Thus, the identity of a cell, and the tasks it is able to carry out, ultimately depend on the regulation of transcription.
While the transcriptional machinery has been studied in great detail, much less is known about the organization of transcription in the three-dimensional space of the nucleus. Transcription in higher eukaryotes takes place in dedicated nuclear compartments called transcription factories. Recent studies have shown that genes “commute” to these factories in order to be transcribed. Furthermore, as the number of active genes (those that are transcribed into RNA) by far outweighs the number of transcription factories, genes must share transcription factories.
To this end, genes undergo dynamic long-range interactions with other genes located on the same chromosome (intra-chromosomal interactions or interactions in cis), or on other chromosomes (inter-chromosomal interactions or interactions in trans) at transcription factories. However, it is unknown how widespread chromosomal interactions are, or what the underlying molecular mechanism is. These questions address a fundamental link between the spatial and the functional organization of transcription in the nucleus.
In this work, we have used the mouse a- and b-globin genes in erythroid cells as a model system to study chromosomal interactions on a genome-wide basis. Surprisingly, we found that chromosomal interactions, in cis and in trans, are widespread. The globin genes undergo associations with hundreds of other active genes, located on all chromosomes, at transcription factories. Remarkably, these associations are non-random, meaning that both globin genes have preferred transcription partners. Among the globin interacting genes, we observed that genes regulated by the transcription factor Klf1 (Kruppel like factor 1) were over-represented. Furthermore, in cells lacking Klf1, interactions between the globin genes and other Klf1-regulated genes were dramatically reduced. Thus, our results show that the transcription factor Klf1is not only required for the efficient transcription of target genes, but also for their three-dimensional clustering in nuclear space.
Klf1 is known to regulate many genes whose protein products are involved in iron uptake into cells, iron transport within cells, heme synthesis, and hemoglobin assembly. The proteins that do this work must appear simultaneously and in just the right amounts in each erythroid cell to make the vital oxygen carrying molecule hemoglobin. Defects in any of the genes in this pathway can lead to clinical symptoms of varying severity, from mild anemia to death.
The interactions between Klf1-regulated genes take place at a subset of transcription factories, which appear to be specialized for the optimal expression of Klf1-regulated genes. This work shows that where genes go in the nucleus, how they are organized in three-dimensional space and how they get there are important parameters that are likely to have a major impact on tissue-specific gene expression programmes. Interestingly, numerous studies have shown that the organization of the nucleus is one of the most obvious changes that occur when cells become cancerous. This previously unappreciated aspect of genome organization in 3D will have important implications in normal health and development as well as disease.
About the lead authors
Stefan Schoenfelder joined the Chromatin and Gene Expression group in 2005, after completing his PhD at the University of Heidelberg, Germany, studying a silencer element involved in genomic imprinting. In Babraham, Stefan works on chromosomal interactions and their role in the three-dimensional organization of transcription.
Tom Sexton started his PhD in the Chromatin and Gene Expression group in 2004, working on genome-wide approaches to mapping chromatin interactions. He completed his PhD in 2008, and is currently working as a postdoctoral researcher at the Institute of Human Genetics in Montpellier.
Lyubomira Chakalova joined the Chromatin and Gene Expression Laboratory at the Babraham Institute in 2000 after completing her PhD at the Institute of Molecular Biology, Bulgaria, where she was working on mammalian DNA repair. In Babraham, Lyubomira worked on a number of projects including developing the TRAP technology, the role of non-coding transcription in globin gene expression regulation and organization of nuclear transcription. She is currently at the Research Centre for Genetic Engineering and Biotechnology in Skopje, Macedonia, working on erythroid differentiation.
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