3D organization of the mammalian genome

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

The human genome project has given us the entire DNA sequence of building blocks of the human genome, but we still know little about how the genome is controlled to express (copy the DNA into RNA) the correct subsets of genes in the different cell types of the body. This proposal will assess for the first time the 3 dimensional arrangement of the entire genome in a particular cell type. Recent scientific evidence suggests that the genome is highly organized within the space of the cell nucleus in such a way as to maximize efficient expression of the desired or required subset of genes while keeping all of the other genes silent. This radically changes the way that scientist think about the genome and gene regulation in general. Genes are not functioning in isolation but preferentially grouping together with other similarly regulated genes to cooperate in their control and efficient expression. The results will have fundamental implications for modern genomic medicines such as gene therapy and stem cell therapies as well as give important clues to health and genetic diseases such as cancer. This knowledge is vitally important to ensure that future genomic and cell therapies are safe, reliable and designed from a position of knowledge and insight rather than trial and error.

Publications

10 25 50
publication icon
Eskiw CH (2010) Transcription factories and nuclear organization of the genome. in Cold Spring Harbor symposia on quantitative biology

publication icon
Schoenfelder S (2010) The transcriptional interactome: gene expression in 3D. in Current opinion in genetics & development

 
Description 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, thus the identity of a cell, and the tasks it is able to carry out, ultimately depend on the regulation of transcription. 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 assembly of 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.

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.