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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.


CTCF flanks chromatin marked by specific histone modifications.(A) Linear representation of a chromosomal region with active and inactive genes, CTCF binding sites and an enhancer (for explanation of symbols, see bottom figure). (B) ChIA-PET reveals different chromatin loops formed by CTCF (Handoko et al., 2011): CTCF loops demarcate regions (1) with active chromatin marks, (2) with inactive chromatin marks, (3) with enhancers and promoters, and (4) with undefined chromatin surrounded by regions with opposing chromatin signatures.
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Figure 3: CTCF flanks chromatin marked by specific histone modifications.(A) Linear representation of a chromosomal region with active and inactive genes, CTCF binding sites and an enhancer (for explanation of symbols, see bottom figure). (B) ChIA-PET reveals different chromatin loops formed by CTCF (Handoko et al., 2011): CTCF loops demarcate regions (1) with active chromatin marks, (2) with inactive chromatin marks, (3) with enhancers and promoters, and (4) with undefined chromatin surrounded by regions with opposing chromatin signatures.

Mentions: ChIA-PET is a technology that combines chromatin immunoprecipitation (ChIP) with a 3C approach, to direct DNA topology studies specifically to the genomic sites that are bound by a protein of interest (Fullwood et al., 2009). ChIA-PET was applied to CTCF to study its DNA interactome (Handoko et al., 2011). Mostly intrachromosomal and a few interchromosomal interactions between CTCF-bound sequences were identified, with the intrachromosomal loop sizes ranging from 10–200 kb. The loops appeared to serve different purposes (Figure 3). They can isolate an active chromatin region from surrounding inactive chromatin or bring together enhancers and promoters in a single loop. Yet other loops formed by CTCF seem to isolate undefined chromatin from a flanking active and inactive chromosomal region (Handoko et al., 2011). Only a few percent of the total number of CTCF sites was found engaged in loop formation. This suggests that ChIA-PET only uncovers the tip of the topological iceberg. Alternatively, the majority of CTCF-bound sites is not involved in long-range chromatin interactions. If the latter is true, it would be interesting to understand what determines whether a CTCF binding site is engaged or not in a chromatin loop.


Chromatin loops, gene positioning, and gene expression.

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

CTCF flanks chromatin marked by specific histone modifications.(A) Linear representation of a chromosomal region with active and inactive genes, CTCF binding sites and an enhancer (for explanation of symbols, see bottom figure). (B) ChIA-PET reveals different chromatin loops formed by CTCF (Handoko et al., 2011): CTCF loops demarcate regions (1) with active chromatin marks, (2) with inactive chromatin marks, (3) with enhancers and promoters, and (4) with undefined chromatin surrounded by regions with opposing chromatin signatures.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: CTCF flanks chromatin marked by specific histone modifications.(A) Linear representation of a chromosomal region with active and inactive genes, CTCF binding sites and an enhancer (for explanation of symbols, see bottom figure). (B) ChIA-PET reveals different chromatin loops formed by CTCF (Handoko et al., 2011): CTCF loops demarcate regions (1) with active chromatin marks, (2) with inactive chromatin marks, (3) with enhancers and promoters, and (4) with undefined chromatin surrounded by regions with opposing chromatin signatures.
Mentions: ChIA-PET is a technology that combines chromatin immunoprecipitation (ChIP) with a 3C approach, to direct DNA topology studies specifically to the genomic sites that are bound by a protein of interest (Fullwood et al., 2009). ChIA-PET was applied to CTCF to study its DNA interactome (Handoko et al., 2011). Mostly intrachromosomal and a few interchromosomal interactions between CTCF-bound sequences were identified, with the intrachromosomal loop sizes ranging from 10–200 kb. The loops appeared to serve different purposes (Figure 3). They can isolate an active chromatin region from surrounding inactive chromatin or bring together enhancers and promoters in a single loop. Yet other loops formed by CTCF seem to isolate undefined chromatin from a flanking active and inactive chromosomal region (Handoko et al., 2011). Only a few percent of the total number of CTCF sites was found engaged in loop formation. This suggests that ChIA-PET only uncovers the tip of the topological iceberg. Alternatively, the majority of CTCF-bound sites is not involved in long-range chromatin interactions. If the latter is true, it would be interesting to understand what determines whether a CTCF binding site is engaged or not in a chromatin loop.

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.