Limits...
Chromatin loops, gene positioning, and gene expression.

Holwerda S, de Laat W - Front Genet (2012)

Bottom Line: Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus.Proteins set up the 3D configuration of the genome and we will discuss the roles of the key structural organizers CTCF and cohesin, the nuclear lamina and the transcription machinery.We will review studies on gene positioning and propose that cell-specific genome conformations can juxtapose a regulatory sequence on one chromosome to a responsive gene on another chromosome to cause altered gene expression in subpopulations of cells.

View Article: PubMed Central - PubMed

Affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht Utrecht, Netherlands.

ABSTRACT
Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus. We will summarize topological studies performed on four model gene loci: the α- and β-globin gene loci, the antigen receptor loci, the imprinted H19-Igf2 locus and the Hox gene clusters. Collectively, these studies show that regulatory DNA sequences physically contact genes to control their transcription. Proteins set up the 3D configuration of the genome and we will discuss the roles of the key structural organizers CTCF and cohesin, the nuclear lamina and the transcription machinery. Finally, genes adopt non-random positions in the nuclear interior. We will review studies on gene positioning and propose that cell-specific genome conformations can juxtapose a regulatory sequence on one chromosome to a responsive gene on another chromosome to cause altered gene expression in subpopulations of cells.

No MeSH data available.


Related in: MedlinePlus

Topological boundaries can act as barriers for spreading of heterochromatin. The 2D heat map shows the Hi-C interaction frequency in human ES cells. Underneath is indicated the directionality index (DI) in hESCs and IMR90 cells. The DI is a Hi-C measure showing a site’s preference to engage in unidirectional contacts with downstream (red) or upstream (green) sequences. Borders of the topological domains are defined by a change in the directionality of interactions (transition from green to red). The UCSC Genome Browser shots show the distribution of H3K9me3, a measure for heterochromatin formation. Note that in IMR90 cells heterochromatin stops at the topological boundaries. Reprinted by permission from Macmillan Publishers Ltd (Dixon et al., 2012), copyright (2012).
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Figure 2: Topological boundaries can act as barriers for spreading of heterochromatin. The 2D heat map shows the Hi-C interaction frequency in human ES cells. Underneath is indicated the directionality index (DI) in hESCs and IMR90 cells. The DI is a Hi-C measure showing a site’s preference to engage in unidirectional contacts with downstream (red) or upstream (green) sequences. Borders of the topological domains are defined by a change in the directionality of interactions (transition from green to red). The UCSC Genome Browser shots show the distribution of H3K9me3, a measure for heterochromatin formation. Note that in IMR90 cells heterochromatin stops at the topological boundaries. Reprinted by permission from Macmillan Publishers Ltd (Dixon et al., 2012), copyright (2012).

Mentions: The most dominant force shaping the 3D genome seems the spatial separation between active and inactive chromatin. First observed under the microscope as a general feature of nuclear organization, it was then confirmed to also be relevant for the folding of individual chromosome segments (Shopland et al., 2006) and, at much higher resolution, for the genomic environments of individual genes (Simonis et al., 2006). The latter observation made by 4C technology for a few selected chromosomal sites was confirmed to apply to regions across the genome by recent Hi-C studies. In Hi-C, all versus all interactions of the genome are mapped, with the resolution of contact maps depending on the depth of sequencing, the size of the genome, and the complexity of the sample analyzed (Lieberman-Aiden et al., 2009; Yaffe and Tanay, 2011; Dixon et al., 2012; Kalhor et al., 2012). Hi-C studies showed that chromosomes are subdivided into topological domains that cover 0.2–1 Mb. The domains mark chromosomal regions within which DNA contacts are confined. They generally demarcate regions with a defined gene density and activity, and with corresponding chromatin accessibility, histone modifications, and replication timing. Preferred contacts among two types of topological domains are seen, the active and inactive topological domains, with the separation of active and inactive chromatin in the nucleus as a consequence (Lieberman-Aiden et al., 2009; Yaffe and Tanay, 2011; Dixon et al., 2012; Kalhor et al., 2012; Nora et al., 2012). In Drosophila in particular, an additional domain type hallmarked by the association of polycomb group (PcG) proteins is observed, which also shows preferred contacts with other PcG-bound topological domains (Tolhuis et al., 2011; Sexton et al., 2012). Marks for active chromatin (DNase I sensitivity, H3K4me1 and -me3, RNAPII) were enriched for regions showing also interchromosomal DNA contacts (Yaffe and Tanay, 2011; Kalhor et al., 2012), suggesting that open and active chromatin most easily reaches out of the CT. Boundaries of the domains were found enriched for CTCF, H3K4me1, transcriptional start sites (TSSs) and housekeeping genes, tRNA genes and SINE elements (Yaffe and Tanay, 2011; Dixon et al., 2012; Sexton et al., 2012). Interestingly, during cellular differentiation the topological domains appear to largely remain intact and structural changes mostly occur within the domains, suggesting that the domain boundaries are largely conserved between cell types (Dixon et al., 2012; Figure 2). The active and inactive compartments each seem to organize themselves independently. This was shown in studies on the active and inactive X chromosome in mammalian female cells, where the inactive X chromosome showed normal contacts between active chromatin regions but was found to specifically lack long-range contacts between inactive chromatin domains. Interestingly, these latter contacts were restored when the non-coding RNA Xist, which coats the inactive X chromosome, was deleted, implicating a role also for non-coding RNA in chromosome topology (Splinter et al., 2011).


Chromatin loops, gene positioning, and gene expression.

Holwerda S, de Laat W - Front Genet (2012)

Topological boundaries can act as barriers for spreading of heterochromatin. The 2D heat map shows the Hi-C interaction frequency in human ES cells. Underneath is indicated the directionality index (DI) in hESCs and IMR90 cells. The DI is a Hi-C measure showing a site’s preference to engage in unidirectional contacts with downstream (red) or upstream (green) sequences. Borders of the topological domains are defined by a change in the directionality of interactions (transition from green to red). The UCSC Genome Browser shots show the distribution of H3K9me3, a measure for heterochromatin formation. Note that in IMR90 cells heterochromatin stops at the topological boundaries. Reprinted by permission from Macmillan Publishers Ltd (Dixon et al., 2012), copyright (2012).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3473233&req=5

Figure 2: Topological boundaries can act as barriers for spreading of heterochromatin. The 2D heat map shows the Hi-C interaction frequency in human ES cells. Underneath is indicated the directionality index (DI) in hESCs and IMR90 cells. The DI is a Hi-C measure showing a site’s preference to engage in unidirectional contacts with downstream (red) or upstream (green) sequences. Borders of the topological domains are defined by a change in the directionality of interactions (transition from green to red). The UCSC Genome Browser shots show the distribution of H3K9me3, a measure for heterochromatin formation. Note that in IMR90 cells heterochromatin stops at the topological boundaries. Reprinted by permission from Macmillan Publishers Ltd (Dixon et al., 2012), copyright (2012).
Mentions: The most dominant force shaping the 3D genome seems the spatial separation between active and inactive chromatin. First observed under the microscope as a general feature of nuclear organization, it was then confirmed to also be relevant for the folding of individual chromosome segments (Shopland et al., 2006) and, at much higher resolution, for the genomic environments of individual genes (Simonis et al., 2006). The latter observation made by 4C technology for a few selected chromosomal sites was confirmed to apply to regions across the genome by recent Hi-C studies. In Hi-C, all versus all interactions of the genome are mapped, with the resolution of contact maps depending on the depth of sequencing, the size of the genome, and the complexity of the sample analyzed (Lieberman-Aiden et al., 2009; Yaffe and Tanay, 2011; Dixon et al., 2012; Kalhor et al., 2012). Hi-C studies showed that chromosomes are subdivided into topological domains that cover 0.2–1 Mb. The domains mark chromosomal regions within which DNA contacts are confined. They generally demarcate regions with a defined gene density and activity, and with corresponding chromatin accessibility, histone modifications, and replication timing. Preferred contacts among two types of topological domains are seen, the active and inactive topological domains, with the separation of active and inactive chromatin in the nucleus as a consequence (Lieberman-Aiden et al., 2009; Yaffe and Tanay, 2011; Dixon et al., 2012; Kalhor et al., 2012; Nora et al., 2012). In Drosophila in particular, an additional domain type hallmarked by the association of polycomb group (PcG) proteins is observed, which also shows preferred contacts with other PcG-bound topological domains (Tolhuis et al., 2011; Sexton et al., 2012). Marks for active chromatin (DNase I sensitivity, H3K4me1 and -me3, RNAPII) were enriched for regions showing also interchromosomal DNA contacts (Yaffe and Tanay, 2011; Kalhor et al., 2012), suggesting that open and active chromatin most easily reaches out of the CT. Boundaries of the domains were found enriched for CTCF, H3K4me1, transcriptional start sites (TSSs) and housekeeping genes, tRNA genes and SINE elements (Yaffe and Tanay, 2011; Dixon et al., 2012; Sexton et al., 2012). Interestingly, during cellular differentiation the topological domains appear to largely remain intact and structural changes mostly occur within the domains, suggesting that the domain boundaries are largely conserved between cell types (Dixon et al., 2012; Figure 2). The active and inactive compartments each seem to organize themselves independently. This was shown in studies on the active and inactive X chromosome in mammalian female cells, where the inactive X chromosome showed normal contacts between active chromatin regions but was found to specifically lack long-range contacts between inactive chromatin domains. Interestingly, these latter contacts were restored when the non-coding RNA Xist, which coats the inactive X chromosome, was deleted, implicating a role also for non-coding RNA in chromosome topology (Splinter et al., 2011).

Bottom Line: Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus.Proteins set up the 3D configuration of the genome and we will discuss the roles of the key structural organizers CTCF and cohesin, the nuclear lamina and the transcription machinery.We will review studies on gene positioning and propose that cell-specific genome conformations can juxtapose a regulatory sequence on one chromosome to a responsive gene on another chromosome to cause altered gene expression in subpopulations of cells.

View Article: PubMed Central - PubMed

Affiliation: Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, University Medical Center Utrecht Utrecht, Netherlands.

ABSTRACT
Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus. We will summarize topological studies performed on four model gene loci: the α- and β-globin gene loci, the antigen receptor loci, the imprinted H19-Igf2 locus and the Hox gene clusters. Collectively, these studies show that regulatory DNA sequences physically contact genes to control their transcription. Proteins set up the 3D configuration of the genome and we will discuss the roles of the key structural organizers CTCF and cohesin, the nuclear lamina and the transcription machinery. Finally, genes adopt non-random positions in the nuclear interior. We will review studies on gene positioning and propose that cell-specific genome conformations can juxtapose a regulatory sequence on one chromosome to a responsive gene on another chromosome to cause altered gene expression in subpopulations of cells.

No MeSH data available.


Related in: MedlinePlus