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

Long-range transcriptional regulation at model gene loci.(A) At the active β-globin locus, LCR–gene contacts and interactions between flanking CTCF sites set up an active chromatin hub (ACH). (B) The IGCR1 contacts the 3′ regulatory region and the intronic enhancer of the IgH locus in pro-B cells. Inclusion of the distal V genes is influenced by the presence of the IGCR1. (C) CTCF blocks the interaction of the Igf2/H19 enhancer with the Igf2 gene on the maternal allele. Methylation of the ICR prevents CTCF binding and enables Igf2 expression from the paternal allele. (D) A “regulatory archipelago” controls the expression of the hoxd13–hoxd10 genes over distance in limb extremities.
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Figure 1: Long-range transcriptional regulation at model gene loci.(A) At the active β-globin locus, LCR–gene contacts and interactions between flanking CTCF sites set up an active chromatin hub (ACH). (B) The IGCR1 contacts the 3′ regulatory region and the intronic enhancer of the IgH locus in pro-B cells. Inclusion of the distal V genes is influenced by the presence of the IGCR1. (C) CTCF blocks the interaction of the Igf2/H19 enhancer with the Igf2 gene on the maternal allele. Methylation of the ICR prevents CTCF binding and enables Igf2 expression from the paternal allele. (D) A “regulatory archipelago” controls the expression of the hoxd13–hoxd10 genes over distance in limb extremities.

Mentions: Early evidence for chromatin looping being involved in mammalian gene regulation comes from studies on the β-globin locus. This is perhaps unsurprising as the globin loci have always been the subject of intense gene expression studies: their misregulation underlies thalassemia and the α- and β-globin genes serve as model systems to study developmental gene regulation. As pointed out, the observation that the deletion of sequences away from, but not affecting, the genes proper caused thalassemia (Van der Ploegh et al., 1980) first suggested that gene transcription was controlled by remote regulatory sequences. A series of remote regulatory sites were then demonstrated to exist in these loci, the most important ones in the β-globin locus collectively referred to as a locus control region (LCR). The LCR controls expression of multiple β-globin genes which are arranged on the chromosome in order of their timed expression during development: embryonic β-globin genes are closest to and adult genes are furthest away from the LCR (Figure 1A). Proximity on the linear DNA template therefore clearly matters, but the exact mode of LCR action over distance long remained elusive. 3D proximity was implicated in transcription regulation when it was found that linear proximity is no longer important when two genes are positioned together at a large distance from the LCR (Hanscombe et al., 1991; Dillon et al., 1997). In 2002, first direct evidence for chromatin looping and spatial contacts between the LCR and an active β-globin gene was obtained, in studies using RNA TRAP (Carter et al., 2002) and 3C technology (Tolhuis et al., 2002). 3C technology in particular appeared extremely useful for further investigations on the topology of the β-globin locus.


Chromatin loops, gene positioning, and gene expression.

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

Long-range transcriptional regulation at model gene loci.(A) At the active β-globin locus, LCR–gene contacts and interactions between flanking CTCF sites set up an active chromatin hub (ACH). (B) The IGCR1 contacts the 3′ regulatory region and the intronic enhancer of the IgH locus in pro-B cells. Inclusion of the distal V genes is influenced by the presence of the IGCR1. (C) CTCF blocks the interaction of the Igf2/H19 enhancer with the Igf2 gene on the maternal allele. Methylation of the ICR prevents CTCF binding and enables Igf2 expression from the paternal allele. (D) A “regulatory archipelago” controls the expression of the hoxd13–hoxd10 genes over distance in limb extremities.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Long-range transcriptional regulation at model gene loci.(A) At the active β-globin locus, LCR–gene contacts and interactions between flanking CTCF sites set up an active chromatin hub (ACH). (B) The IGCR1 contacts the 3′ regulatory region and the intronic enhancer of the IgH locus in pro-B cells. Inclusion of the distal V genes is influenced by the presence of the IGCR1. (C) CTCF blocks the interaction of the Igf2/H19 enhancer with the Igf2 gene on the maternal allele. Methylation of the ICR prevents CTCF binding and enables Igf2 expression from the paternal allele. (D) A “regulatory archipelago” controls the expression of the hoxd13–hoxd10 genes over distance in limb extremities.
Mentions: Early evidence for chromatin looping being involved in mammalian gene regulation comes from studies on the β-globin locus. This is perhaps unsurprising as the globin loci have always been the subject of intense gene expression studies: their misregulation underlies thalassemia and the α- and β-globin genes serve as model systems to study developmental gene regulation. As pointed out, the observation that the deletion of sequences away from, but not affecting, the genes proper caused thalassemia (Van der Ploegh et al., 1980) first suggested that gene transcription was controlled by remote regulatory sequences. A series of remote regulatory sites were then demonstrated to exist in these loci, the most important ones in the β-globin locus collectively referred to as a locus control region (LCR). The LCR controls expression of multiple β-globin genes which are arranged on the chromosome in order of their timed expression during development: embryonic β-globin genes are closest to and adult genes are furthest away from the LCR (Figure 1A). Proximity on the linear DNA template therefore clearly matters, but the exact mode of LCR action over distance long remained elusive. 3D proximity was implicated in transcription regulation when it was found that linear proximity is no longer important when two genes are positioned together at a large distance from the LCR (Hanscombe et al., 1991; Dillon et al., 1997). In 2002, first direct evidence for chromatin looping and spatial contacts between the LCR and an active β-globin gene was obtained, in studies using RNA TRAP (Carter et al., 2002) and 3C technology (Tolhuis et al., 2002). 3C technology in particular appeared extremely useful for further investigations on the topology of the β-globin locus.

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