- Email: [email protected]
Differentiation and gene regulation
Differentiation and gene regulation Editorial overview Frank G Grosveld and Denis Duboule Current Opinion in Genetics & Development 2007, 17:369–372
0959-437X/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. DOI 10.1016/j.gde.2007.10.001
Frank G Grosveld Department of Cell Biology, Erasmus Medical Centre, Rotterdam, The Netherlands e-mail: [email protected]
Frank Grosveld is a professor of Cell Biology at the Erasmus Medical Center in Rotterdam. He is a biochemist and molecular biologist by training and is active in the field of gene regulation in mammalian development and disease. He is a member of two EU networks of excellence ‘‘the Epigenome’’ and ‘‘Cells into Organs’’ and the worldwide consortium ‘‘the International Regulome’’ that aims to characterise all transcription factor complexes, and which includes coordination of the EU integrated project ‘‘EUTRACC’’. Denis Duboule National Research Centre ‘Frontiers in Genetics’, Department of Zoology and Animal Biology, University of Geneva, Sciences III and School of Life Sciences, Federal Institute of Technology, Lausanne, Switzerland e-mail: [email protected]
Denis Duboule is professor of Developmental genetics and genomics at the University of Geneva and the Federal Institute of Technology in Lausanne. He is the chair of the Swiss National Centre ‘Frontiers in Genetics’ and is active in the fields of developmental genetics of vertebrates, in particular concerning large scale gene regulation, in an evolutionnary context.
Introduction Over the past 30 years, our views on the mechanisms underlying gene regulation have changed considerably. It is now well accepted that, in order for a transcription unit to be properly regulated, not only should the requested DNA sequence-specific factors and complexes thereof be present, but also the micro-environmental conditions, in terms of local chromatin configuration, should be appropriate. The global organization of chromosomes and the dynamics of the genome in the nucleus are equally important and have been a focus of attention since the beginning of the 20th century (e.g. Wilson 1905 [4]). Although a lot of progress on the basic principles and processes was made, it remained very difficult to study the interactions that take place in the genome. However, with the advance of new technologies and a spectacular increase in the size of the toolbox available to present day investigators, it has only fairly recently become possible to study the nucleus at the level of resolution required to measure or visualize interactions and the movement of individual gene loci or whole chromosomes. As a result recent developments have been fast and furious, covering a range of interests from studies on the role of single proteins to the analysis of the interactions between complete chromosomes. This fast pace inevitably leads to contradictory observations and it is sometimes difficult to distinguish fact from fiction, particularly when novel technologies are used or when techniques depend on the eye of the investigator, as is the case in a number of microscopic techniques. Nevertheless, the study of nuclear organization and dynamics is an interesting and exciting area of research aiming to understand how the cell ‘organizes’ a large genome into the small space of the nucleus; which mechanisms it uses to regulate the expression of the genome while maintaining the flexibility to respond to cues coming from other cells or from the environment; and how the cell duplicates and divides the genome into two daughter genomes. One of the most debated issues in the field is whether nuclear structure adheres to some ‘masterplan’ or ‘design’ or whether its organization is based on stochastic principles and dependent on the remarkable properties of macromolecules and macromolecular complexes. The reviews in this issue of Current Opinion discuss novel concepts and technologies associated with the control of gene expression during development, as viewed from different angles. Topics range from examining basic physical principals relevant to nuclear organization to the review of proteins involved in genomic interactions and the (dynamics of) interactions within a chromosome and between chromosomes.
Organizing principles and genome variation The nucleus is organized in sub-compartments with distinct biological activities, which represents an important regulatory layer for cell function.
www.sciencedirect.com
Current Opinion in Genetics & Development 2007, 17:369–372
370 Differentiation and gene regulation
Karsten Rippe discusses new insights into the principles by which nuclear organelles form. This usually occurs in a self-organising manner based on the specific physical properties of macromolecular complexes, leading to the formation of stable but plastic structures involving multiple, yet relatively weak, interactions. Changes in the nuclear environment or, alternatively, addition, deletion or modification of individual components can rearrange such structures leading to a different functional state. Importantly, it describes how movement within the nucleus or even at the level of a chromosome can take place without the involvement of a directed force such as for example provided by motor proteins. The genome itself is not a fixed entity with small variations and recent work has shown that large stretches of the genome can vary considerably. Alexandre Reymond, Charlotte N. Henrichsen, Louise Harewood and Giuseppe Merla review the first extensive catalogue of structural human variations that was recently released. It showed that copy number variation in large stretches of the genome is extremely abundant, raising the possibility that they play a major role in functional variation. Genomic insertions and deletions obviously contribute to phenotypic differences by modifying the expression levels of genes within the aneuploid segments. Interestingly, however, such variations also influence the expression of neighbouring genes present in normal copy numbers and the authors discuss the possible mechanisms behind this latter effect. Structural properties of the genome can also be altered by modifications of the chromatin. Anton Wutz and Joost Gribnau discuss the most dramatic example of epigenetic modification of the genome, X inactivation, which in mammals leads to an almost separate domain within the nucleus. Inactivation of one of the two female X chromosomes is essential to establish dosage compensation between XY males and XX females in placental mammals. The choice of X inactivation is random and is controlled by the X inactivation center (Xic). Recent advances in genome sequencing show that the Xic has evolved from an ancestral vertebrate gene cluster in placental mammals and underwent separate rearrangements in marsupials. The Xic ensures that all but one X chromosome per diploid genome are inactivated. Pairing of Xic loci on the two X chromosomes and alternate states of the X chromosomes before inactivation have recently been implicated in the mechanism of random choice. Chromosome-wide silencing is then initiated by the non-coding Xist RNA, which evolved with the mammalian Xic and covers the inactive X chromosome.
Interactions within chromosomes loops and boundaries The development of a number of technologies but in particular the Chromosome Conformation Capture (3C) approach (Dekker et al. [2]) adapted to the analysis of Current Opinion in Genetics & Development 2007, 17:369–372
individual loci (Tolhuis et al. [3]) has resulted in a large leap forward in our understanding of how loci are organized in loops. Genetic studies in Drosophila spearheaded the initial ideas and understanding of how loci may be organized in such loops between boundaries and Robert, K. Maeda and Franc¸ois Karch review how regulatory elements can exert their effect over many tens of kilobases of DNA on particular promoters, using chromatin boundaries in the fruit fly. The existence of boundaries was first proposed on the basis of Drosophila genetics. Because these elements are involved in such diverse processes and show little or no sequence homology between each other, no single molecular mechanism could account so far for their activity. Recent evidence nonetheless showed that boundaries probably function through the formation of long-distance chromatin loops. These loops have been proposed to play a crucial role in both controlling enhancer–promoter interactions and packing DNA. The molecular mechanism and some of the molecules involved in loop and boundary formation are discussed by Julie A. Wallace and Gary Felsenfeld, with a special emphasis on two different ‘organizer’ proteins. They review the bestcharacterized elements involved in the separation of functional domains, the gypsy in Drosophila and the CTCF-binding element in vertebrates. These sequences stabilize contacts between distant genomic regulatory sites leading to the formation of looped domains. They discuss CTCF mediating contacts in the mouse b-globin locus and, at the Igf2/H19 imprinted locus, the formation of active chromatin hubs and transcription factories. The properties of CTCF, most of which is stably bound to the chromatin, and its recently described genomic distribution, suggest that it plays an important role in nuclear architecture. Sanjeev Galande, Prabhat Kumar Purbey, Dimple Notani, and Pavan Kumar describe the role of another nuclear ‘organiser’ protein, SATB1. They discuss the function of SatB1 as a key factor for the integration of higher-order chromatin architecture with gene regulation. SATB1 organizes the MHC class-I locus into distinct chromatin loops and plays a key role in the response to physiological stimuli. At a genome-wide level, SATB1 seems to act as an organizer of transcriptionally poised chromatin.
Regulation within large domains The structure/function organization of some large loci, which heavily depend on looping factors, is discussed next. Cornelis Murre reviews the control of immunoglobulin gene rearrangement. This locus extends over more than 1.5 Mb and is of interest from an organizational point of view. At early stages of B cell development, one of the variable regions is recombined with the D, J and constant regions in a process known as VDJ recombination. A key aspect of this process is how distant V regions can recombine with efficiencies similar to those seen for the V www.sciencedirect.com
Editorial overview Grosveld and Duboule 371
regions that are located much closer to D and J. Much is known about the control of its transcription and epigenetic remodelling but it is only recently that data are emerging which suggest that there is an underlying structural order that facilitates the association of DNA elements separated by large genomic distances. Another well-known example of the importance of gene proximity for shared and coherent transcriptional regulation is provided by the Hox gene family. In vertebrates, these genes are organized in tight genomic clusters and instruct early embryonic tissues about their positional identities in a process called patterning. Jacqueline Deschamps discusses the relationship between clustering and gene regulation. Hox gene clustering is one of the most interesting aspects of their functioning because the order of the genes in each cluster largely reflects the anterior to posterior order of their expression in the early embryo. This link between gene order and order of expression, termed collinearity, originated early during evolution and has been conserved from flies to human. Deschamps reviews how murine Hox genes are regulated in part by gene-proximal regulatory elements, but interestingly how several of their essential spatial expression properties are dependent on global regulatory elements located outside the complexes, leading to the notion of ‘regulatory landscape’. Another regulatory landscape crucial for proper vertebrate development is reviewed by Rolf Zeller and Aime´e Zuniga, who discuss the process of patterning from a different perspective, that of limb development. During this process, two regulatory signals play essential roles in digit patterning, the Shh morphogen and the BMP antagonist Gremlin1. Their expression patterns are very dynamic and regulated by cis-regulatory elements embedded in unrelated and remote neighbouring genes. Malfunction of elements that can be located at megabase distances from the gene are the primary cause of different types of congenital limb malformations. Recent comparative and functional genomics studies have uncovered large and complex chromosomal landscapes controlling these genes, in which some HOX products play an important role.
Chromatin mobility One of the most interesting, yet hotly debated, issue relates to the mobility of the genome and is reviewed by Evi Soutoglou and Tom Misteli. They describe how chromatin is increasingly recognized as a highly dynamic entity. Chromosome sites, in both lower and higher eukaryotes, undergo frequent, rapid and constrained local motion and occasional slow, long-range movements. While the dynamic properties of chromatin have been described by visualization in vivo, some of the functional relevance of chromatin mobility has only recently become clear. Both the mobility and immobility of chromatin www.sciencedirect.com
appears to have functional consequences: local (diffusion-based) motion of chromatin is important in gene regulation, yet global chromatin immobility appears to play a key role in maintenance of genomic stability.
Interactions between chromosomes The interactions between chromosomes and between chromosomes and the nuclear envelop have recently become a focus of intensive studies. Giacomo Cavalli reviews how chromosomes occupy distinct territories in the cell nucleus, but that these territories can intermingle with one another. Most functional genomic interactions appear to occur in cis with neighbouring elements. However, many inter-chromosomal contacts have also been documented, though the functional relevance of such contacts (referred to as ‘chromosome kissing’) is still unclear. Most contacts will inevitably arise because chromosomes happen to lie next to each other or because genes share common machineries such as those required for transcription and splicing. Such neighbouring contacts are likely to be important in chromosomal rearrangements and some appear to have specific regulatory functions. Ana Pombo and Miguel R. Branco use their expertise in imaging techniques to further review in detail such interchromosomal interactions. The first high-throughput mapping of chromosome architecture in specific cell types is currently in progress and such maps may help our understanding of the mechanisms by which genome architecture regulate gene expression. They discuss how the (linear) genome may segregate into domains that are more or less permissive for transcription within the three-dimensional nucleus, and how the position of a gene within the nucleus can enhance its activation or silencing or even the efficiency by which its products are processed or transported to the cytoplasm. As a number of recent reports suggest that inter-chromosomal DNA interactions mediate the decision of which allele to activate and which to silence, Wouter de Laat and Frank Grosveld review functional inter-chromosomal contacts in the context of mono-allelic gene expression. They discuss these findings in relation to our knowledge on gene competition, chromatin dynamics and nuclear organization. They argue that both microscopy and biochemical (4C) data strongly support the idea whereby chromatin folds according to self-organizing principles and that the nuclear positioning of a given locus is probabilistic because it also depends on the properties of neighbouring DNA segments. They further argue that this stochastic concept of nuclear organization implies that tissue-specific interactions between two selected loci, present on different chromosomes, will be rare. Finally, Ivan Rodriguez reviews the transcriptional control of the largest mammalian gene family, the odorant receptor genes. The members of this family are located in large gene clusters, located on different chromosomes and are often interspersed by other genes and regulatory Current Opinion in Genetics & Development 2007, 17:369–372
372 Differentiation and gene regulation
regions. Interestingly, olfactory sensory neurons express only a single odorant receptor gene from a single parental allele and represent a most extreme form of monoallelic expression. How this is achieved is unknown, but recent work points to multiple regulatory mechanisms, that may also involve the interaction between loci located on different chromosomes.
amount of data quickly is expected to lead to even more rapid progress in our understanding of the structure and dynamics of the genome.
Conclusions
References
As these reviews illustrate, there is rapid progress in the analysis of the behaviour of the genome. With increasingly more ‘high-throughput’ whole genome techniques and more sensitive proteomics, in particular mass spectrometry, the analysis of individual proteins can be unravelled more quickly and in more detail. In parallel, improved imaging via new microscopic techniques (particularly in the range of 5–200 nm, for review see Cremer and Cremer [1]) and more sophisticated and bright labels for visualisation are rapidly being developed. Finally, the improvements on the informatics and mathematical side to process, interpret and model the vast
1.
Cremer T, Cremer C: Rise, fall and resurrection of chromosome territories: a historical perspective. Part II. Fall and resurrection of chromosome territories during the 1950s to 1980s. Part III. Chromosome territories and the functional nuclear architecture: experiments and models from the 1990s to the present. Eur J Histochem 2006, 50(4):223-272.
2.
Dekker J, Rippe K, Dekker M, Kleckner N: Capturing chromosome conformation. Science 2002, 295(5558):13061311.
3.
Tolhuis B, Palstra RJ, Splinter E, Grosveld F, de Laat W: Looping and interaction between hypersensitive sites in the active beta-globin locus. Mol Cell 2002, 10(6):1453-1465.
4.
Wilson EB: The chromosomes in relation to the determination of sex in insects. Science 1905, 22(564):500-502.
Current Opinion in Genetics & Development 2007, 17:369–372
Acknowledgements FG and DD are members of — and supported by — the EU FP6 programme ‘Cells into Organs’.
www.sciencedirect.com
0959-437X/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. DOI 10.1016/j.gde.2007.10.001
Frank G Grosveld Department of Cell Biology, Erasmus Medical Centre, Rotterdam, The Netherlands e-mail: [email protected]
Frank Grosveld is a professor of Cell Biology at the Erasmus Medical Center in Rotterdam. He is a biochemist and molecular biologist by training and is active in the field of gene regulation in mammalian development and disease. He is a member of two EU networks of excellence ‘‘the Epigenome’’ and ‘‘Cells into Organs’’ and the worldwide consortium ‘‘the International Regulome’’ that aims to characterise all transcription factor complexes, and which includes coordination of the EU integrated project ‘‘EUTRACC’’. Denis Duboule National Research Centre ‘Frontiers in Genetics’, Department of Zoology and Animal Biology, University of Geneva, Sciences III and School of Life Sciences, Federal Institute of Technology, Lausanne, Switzerland e-mail: [email protected]
Denis Duboule is professor of Developmental genetics and genomics at the University of Geneva and the Federal Institute of Technology in Lausanne. He is the chair of the Swiss National Centre ‘Frontiers in Genetics’ and is active in the fields of developmental genetics of vertebrates, in particular concerning large scale gene regulation, in an evolutionnary context.
Introduction Over the past 30 years, our views on the mechanisms underlying gene regulation have changed considerably. It is now well accepted that, in order for a transcription unit to be properly regulated, not only should the requested DNA sequence-specific factors and complexes thereof be present, but also the micro-environmental conditions, in terms of local chromatin configuration, should be appropriate. The global organization of chromosomes and the dynamics of the genome in the nucleus are equally important and have been a focus of attention since the beginning of the 20th century (e.g. Wilson 1905 [4]). Although a lot of progress on the basic principles and processes was made, it remained very difficult to study the interactions that take place in the genome. However, with the advance of new technologies and a spectacular increase in the size of the toolbox available to present day investigators, it has only fairly recently become possible to study the nucleus at the level of resolution required to measure or visualize interactions and the movement of individual gene loci or whole chromosomes. As a result recent developments have been fast and furious, covering a range of interests from studies on the role of single proteins to the analysis of the interactions between complete chromosomes. This fast pace inevitably leads to contradictory observations and it is sometimes difficult to distinguish fact from fiction, particularly when novel technologies are used or when techniques depend on the eye of the investigator, as is the case in a number of microscopic techniques. Nevertheless, the study of nuclear organization and dynamics is an interesting and exciting area of research aiming to understand how the cell ‘organizes’ a large genome into the small space of the nucleus; which mechanisms it uses to regulate the expression of the genome while maintaining the flexibility to respond to cues coming from other cells or from the environment; and how the cell duplicates and divides the genome into two daughter genomes. One of the most debated issues in the field is whether nuclear structure adheres to some ‘masterplan’ or ‘design’ or whether its organization is based on stochastic principles and dependent on the remarkable properties of macromolecules and macromolecular complexes. The reviews in this issue of Current Opinion discuss novel concepts and technologies associated with the control of gene expression during development, as viewed from different angles. Topics range from examining basic physical principals relevant to nuclear organization to the review of proteins involved in genomic interactions and the (dynamics of) interactions within a chromosome and between chromosomes.
Organizing principles and genome variation The nucleus is organized in sub-compartments with distinct biological activities, which represents an important regulatory layer for cell function.
www.sciencedirect.com
Current Opinion in Genetics & Development 2007, 17:369–372
370 Differentiation and gene regulation
Karsten Rippe discusses new insights into the principles by which nuclear organelles form. This usually occurs in a self-organising manner based on the specific physical properties of macromolecular complexes, leading to the formation of stable but plastic structures involving multiple, yet relatively weak, interactions. Changes in the nuclear environment or, alternatively, addition, deletion or modification of individual components can rearrange such structures leading to a different functional state. Importantly, it describes how movement within the nucleus or even at the level of a chromosome can take place without the involvement of a directed force such as for example provided by motor proteins. The genome itself is not a fixed entity with small variations and recent work has shown that large stretches of the genome can vary considerably. Alexandre Reymond, Charlotte N. Henrichsen, Louise Harewood and Giuseppe Merla review the first extensive catalogue of structural human variations that was recently released. It showed that copy number variation in large stretches of the genome is extremely abundant, raising the possibility that they play a major role in functional variation. Genomic insertions and deletions obviously contribute to phenotypic differences by modifying the expression levels of genes within the aneuploid segments. Interestingly, however, such variations also influence the expression of neighbouring genes present in normal copy numbers and the authors discuss the possible mechanisms behind this latter effect. Structural properties of the genome can also be altered by modifications of the chromatin. Anton Wutz and Joost Gribnau discuss the most dramatic example of epigenetic modification of the genome, X inactivation, which in mammals leads to an almost separate domain within the nucleus. Inactivation of one of the two female X chromosomes is essential to establish dosage compensation between XY males and XX females in placental mammals. The choice of X inactivation is random and is controlled by the X inactivation center (Xic). Recent advances in genome sequencing show that the Xic has evolved from an ancestral vertebrate gene cluster in placental mammals and underwent separate rearrangements in marsupials. The Xic ensures that all but one X chromosome per diploid genome are inactivated. Pairing of Xic loci on the two X chromosomes and alternate states of the X chromosomes before inactivation have recently been implicated in the mechanism of random choice. Chromosome-wide silencing is then initiated by the non-coding Xist RNA, which evolved with the mammalian Xic and covers the inactive X chromosome.
Interactions within chromosomes loops and boundaries The development of a number of technologies but in particular the Chromosome Conformation Capture (3C) approach (Dekker et al. [2]) adapted to the analysis of Current Opinion in Genetics & Development 2007, 17:369–372
individual loci (Tolhuis et al. [3]) has resulted in a large leap forward in our understanding of how loci are organized in loops. Genetic studies in Drosophila spearheaded the initial ideas and understanding of how loci may be organized in such loops between boundaries and Robert, K. Maeda and Franc¸ois Karch review how regulatory elements can exert their effect over many tens of kilobases of DNA on particular promoters, using chromatin boundaries in the fruit fly. The existence of boundaries was first proposed on the basis of Drosophila genetics. Because these elements are involved in such diverse processes and show little or no sequence homology between each other, no single molecular mechanism could account so far for their activity. Recent evidence nonetheless showed that boundaries probably function through the formation of long-distance chromatin loops. These loops have been proposed to play a crucial role in both controlling enhancer–promoter interactions and packing DNA. The molecular mechanism and some of the molecules involved in loop and boundary formation are discussed by Julie A. Wallace and Gary Felsenfeld, with a special emphasis on two different ‘organizer’ proteins. They review the bestcharacterized elements involved in the separation of functional domains, the gypsy in Drosophila and the CTCF-binding element in vertebrates. These sequences stabilize contacts between distant genomic regulatory sites leading to the formation of looped domains. They discuss CTCF mediating contacts in the mouse b-globin locus and, at the Igf2/H19 imprinted locus, the formation of active chromatin hubs and transcription factories. The properties of CTCF, most of which is stably bound to the chromatin, and its recently described genomic distribution, suggest that it plays an important role in nuclear architecture. Sanjeev Galande, Prabhat Kumar Purbey, Dimple Notani, and Pavan Kumar describe the role of another nuclear ‘organiser’ protein, SATB1. They discuss the function of SatB1 as a key factor for the integration of higher-order chromatin architecture with gene regulation. SATB1 organizes the MHC class-I locus into distinct chromatin loops and plays a key role in the response to physiological stimuli. At a genome-wide level, SATB1 seems to act as an organizer of transcriptionally poised chromatin.
Regulation within large domains The structure/function organization of some large loci, which heavily depend on looping factors, is discussed next. Cornelis Murre reviews the control of immunoglobulin gene rearrangement. This locus extends over more than 1.5 Mb and is of interest from an organizational point of view. At early stages of B cell development, one of the variable regions is recombined with the D, J and constant regions in a process known as VDJ recombination. A key aspect of this process is how distant V regions can recombine with efficiencies similar to those seen for the V www.sciencedirect.com
Editorial overview Grosveld and Duboule 371
regions that are located much closer to D and J. Much is known about the control of its transcription and epigenetic remodelling but it is only recently that data are emerging which suggest that there is an underlying structural order that facilitates the association of DNA elements separated by large genomic distances. Another well-known example of the importance of gene proximity for shared and coherent transcriptional regulation is provided by the Hox gene family. In vertebrates, these genes are organized in tight genomic clusters and instruct early embryonic tissues about their positional identities in a process called patterning. Jacqueline Deschamps discusses the relationship between clustering and gene regulation. Hox gene clustering is one of the most interesting aspects of their functioning because the order of the genes in each cluster largely reflects the anterior to posterior order of their expression in the early embryo. This link between gene order and order of expression, termed collinearity, originated early during evolution and has been conserved from flies to human. Deschamps reviews how murine Hox genes are regulated in part by gene-proximal regulatory elements, but interestingly how several of their essential spatial expression properties are dependent on global regulatory elements located outside the complexes, leading to the notion of ‘regulatory landscape’. Another regulatory landscape crucial for proper vertebrate development is reviewed by Rolf Zeller and Aime´e Zuniga, who discuss the process of patterning from a different perspective, that of limb development. During this process, two regulatory signals play essential roles in digit patterning, the Shh morphogen and the BMP antagonist Gremlin1. Their expression patterns are very dynamic and regulated by cis-regulatory elements embedded in unrelated and remote neighbouring genes. Malfunction of elements that can be located at megabase distances from the gene are the primary cause of different types of congenital limb malformations. Recent comparative and functional genomics studies have uncovered large and complex chromosomal landscapes controlling these genes, in which some HOX products play an important role.
Chromatin mobility One of the most interesting, yet hotly debated, issue relates to the mobility of the genome and is reviewed by Evi Soutoglou and Tom Misteli. They describe how chromatin is increasingly recognized as a highly dynamic entity. Chromosome sites, in both lower and higher eukaryotes, undergo frequent, rapid and constrained local motion and occasional slow, long-range movements. While the dynamic properties of chromatin have been described by visualization in vivo, some of the functional relevance of chromatin mobility has only recently become clear. Both the mobility and immobility of chromatin www.sciencedirect.com
appears to have functional consequences: local (diffusion-based) motion of chromatin is important in gene regulation, yet global chromatin immobility appears to play a key role in maintenance of genomic stability.
Interactions between chromosomes The interactions between chromosomes and between chromosomes and the nuclear envelop have recently become a focus of intensive studies. Giacomo Cavalli reviews how chromosomes occupy distinct territories in the cell nucleus, but that these territories can intermingle with one another. Most functional genomic interactions appear to occur in cis with neighbouring elements. However, many inter-chromosomal contacts have also been documented, though the functional relevance of such contacts (referred to as ‘chromosome kissing’) is still unclear. Most contacts will inevitably arise because chromosomes happen to lie next to each other or because genes share common machineries such as those required for transcription and splicing. Such neighbouring contacts are likely to be important in chromosomal rearrangements and some appear to have specific regulatory functions. Ana Pombo and Miguel R. Branco use their expertise in imaging techniques to further review in detail such interchromosomal interactions. The first high-throughput mapping of chromosome architecture in specific cell types is currently in progress and such maps may help our understanding of the mechanisms by which genome architecture regulate gene expression. They discuss how the (linear) genome may segregate into domains that are more or less permissive for transcription within the three-dimensional nucleus, and how the position of a gene within the nucleus can enhance its activation or silencing or even the efficiency by which its products are processed or transported to the cytoplasm. As a number of recent reports suggest that inter-chromosomal DNA interactions mediate the decision of which allele to activate and which to silence, Wouter de Laat and Frank Grosveld review functional inter-chromosomal contacts in the context of mono-allelic gene expression. They discuss these findings in relation to our knowledge on gene competition, chromatin dynamics and nuclear organization. They argue that both microscopy and biochemical (4C) data strongly support the idea whereby chromatin folds according to self-organizing principles and that the nuclear positioning of a given locus is probabilistic because it also depends on the properties of neighbouring DNA segments. They further argue that this stochastic concept of nuclear organization implies that tissue-specific interactions between two selected loci, present on different chromosomes, will be rare. Finally, Ivan Rodriguez reviews the transcriptional control of the largest mammalian gene family, the odorant receptor genes. The members of this family are located in large gene clusters, located on different chromosomes and are often interspersed by other genes and regulatory Current Opinion in Genetics & Development 2007, 17:369–372
372 Differentiation and gene regulation
regions. Interestingly, olfactory sensory neurons express only a single odorant receptor gene from a single parental allele and represent a most extreme form of monoallelic expression. How this is achieved is unknown, but recent work points to multiple regulatory mechanisms, that may also involve the interaction between loci located on different chromosomes.
amount of data quickly is expected to lead to even more rapid progress in our understanding of the structure and dynamics of the genome.
Conclusions
References
As these reviews illustrate, there is rapid progress in the analysis of the behaviour of the genome. With increasingly more ‘high-throughput’ whole genome techniques and more sensitive proteomics, in particular mass spectrometry, the analysis of individual proteins can be unravelled more quickly and in more detail. In parallel, improved imaging via new microscopic techniques (particularly in the range of 5–200 nm, for review see Cremer and Cremer [1]) and more sophisticated and bright labels for visualisation are rapidly being developed. Finally, the improvements on the informatics and mathematical side to process, interpret and model the vast
1.
Cremer T, Cremer C: Rise, fall and resurrection of chromosome territories: a historical perspective. Part II. Fall and resurrection of chromosome territories during the 1950s to 1980s. Part III. Chromosome territories and the functional nuclear architecture: experiments and models from the 1990s to the present. Eur J Histochem 2006, 50(4):223-272.
2.
Dekker J, Rippe K, Dekker M, Kleckner N: Capturing chromosome conformation. Science 2002, 295(5558):13061311.
3.
Tolhuis B, Palstra RJ, Splinter E, Grosveld F, de Laat W: Looping and interaction between hypersensitive sites in the active beta-globin locus. Mol Cell 2002, 10(6):1453-1465.
4.
Wilson EB: The chromosomes in relation to the determination of sex in insects. Science 1905, 22(564):500-502.
Current Opinion in Genetics & Development 2007, 17:369–372
Acknowledgements FG and DD are members of — and supported by — the EU FP6 programme ‘Cells into Organs’.
www.sciencedirect.com