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Chromatin and epigenetic features of long-range gene regulation.

Harmston N, Lenhard B - Nucleic Acids Res. (2013)

Bottom Line: The movement of enhancers and promoters in and out of higher-order chromatin structures within the nucleus are associated with changes in expression and histone modifications.However, the factors responsible for mediating these changes and determining enhancer:promoter specificity are still not completely known.In this review, we summarize what is known about the patterns of epigenetic and chromatin features characteristic of elements involved in long-range interactions.

View Article: PubMed Central - PubMed

Affiliation: MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London W12 0NN, UK, Institute of Clinical Sciences, Faculty of Medicine, Imperial College, London W12 0NN, UK and Department of Informatics, University of Bergen, Thromøhlensgate 55, N-5008 Bergen, Norway.

ABSTRACT
The precise regulation of gene transcription during metazoan development is controlled by a complex system of interactions between transcription factors, histone modifications and modifying enzymes and chromatin conformation. Developments in chromosome conformation capture technologies have revealed that interactions between regions of chromatin are pervasive and highly cell-type specific. The movement of enhancers and promoters in and out of higher-order chromatin structures within the nucleus are associated with changes in expression and histone modifications. However, the factors responsible for mediating these changes and determining enhancer:promoter specificity are still not completely known. In this review, we summarize what is known about the patterns of epigenetic and chromatin features characteristic of elements involved in long-range interactions. In addition, we review the insights into both local and global patterns of chromatin interactions that have been revealed by the latest experimental and computational methods.

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Chromatin looping is responsible for forming higher-order hub-like structures within the nucleus. (a) An active chromatin hub (ACH) is a structure that allows enhancers and promoters to come into close spatial proximity with each other (40). This structure has a high concentration of chromatin remodellers and PolII, which allows stable/high levels of transcription. Interactions between promoters and enhancers and represented by dashed lines. (b) The recruitment of genes and enhancers to a repressive chromatin hub (RCH) results in their downregulation (165). This structure potentially prevents enhancers from communicating with their cognate promoter by looping them out and preventing them from interacting. This structure may also restrict the amount of PolII from binding to gene promoters. (c and d) During development, genes in the Hox locus show a linear movement from a repressive chromatin structure to a region where they are expressed (166). This movement allows enhancers to interact with targets that were previously held in the repressive domain.
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gkt499-F3: Chromatin looping is responsible for forming higher-order hub-like structures within the nucleus. (a) An active chromatin hub (ACH) is a structure that allows enhancers and promoters to come into close spatial proximity with each other (40). This structure has a high concentration of chromatin remodellers and PolII, which allows stable/high levels of transcription. Interactions between promoters and enhancers and represented by dashed lines. (b) The recruitment of genes and enhancers to a repressive chromatin hub (RCH) results in their downregulation (165). This structure potentially prevents enhancers from communicating with their cognate promoter by looping them out and preventing them from interacting. This structure may also restrict the amount of PolII from binding to gene promoters. (c and d) During development, genes in the Hox locus show a linear movement from a repressive chromatin structure to a region where they are expressed (166). This movement allows enhancers to interact with targets that were previously held in the repressive domain.

Mentions: In erythoid cells, where β-globin is expressed, these interactions form a compartment containing regulatory elements that has a high level of transcriptional activity (40). These chromatin structures depend on sequence-specific TFs bound to both the enhancer and promoter and thus can explain the specificity observed in enhancer:promoter interactions. Knock out of TFs responsible for regulating β-globin expression (EKLF and GATA-1) result in the loss of interactions between the gene and its enhancers, leading to loss of the overall hub-like structure (163,164). Interactions between regulatory elements separated by large genomic distances have been observed at high frequencies at other loci, leading to the proposition that chromatin looping generally results in the formation of hub-like structures. These active chromatin hubs (ACH) are responsible for bringing enhancers and promoters into close spatial proximity as well as providing an environment that is transcriptionally permissive (Figure 3a). The contents of the β-globin ACH changes during differentiation, with the ACH lacking certain elements in progenitor cells, which are found there later during differentiation (167). At the Myb locus during erythoid proliferation, intergenic enhancers, the Myb promoter and its first intron are brought together to form an ACH (168). The ACH leads to high concentrations of PolII and TFs being present around Myb. The first intron of this gene contains a site for regulating transcriptional elongation. Interactions between this element and distal enhancers lead to the generation of full-length transcripts. This structure is lost when cells terminally differentiate, coincident with the loss of expression of Myb and a reduction in TF binding at regulatory elements.Figure 3.


Chromatin and epigenetic features of long-range gene regulation.

Harmston N, Lenhard B - Nucleic Acids Res. (2013)

Chromatin looping is responsible for forming higher-order hub-like structures within the nucleus. (a) An active chromatin hub (ACH) is a structure that allows enhancers and promoters to come into close spatial proximity with each other (40). This structure has a high concentration of chromatin remodellers and PolII, which allows stable/high levels of transcription. Interactions between promoters and enhancers and represented by dashed lines. (b) The recruitment of genes and enhancers to a repressive chromatin hub (RCH) results in their downregulation (165). This structure potentially prevents enhancers from communicating with their cognate promoter by looping them out and preventing them from interacting. This structure may also restrict the amount of PolII from binding to gene promoters. (c and d) During development, genes in the Hox locus show a linear movement from a repressive chromatin structure to a region where they are expressed (166). This movement allows enhancers to interact with targets that were previously held in the repressive domain.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3753629&req=5

gkt499-F3: Chromatin looping is responsible for forming higher-order hub-like structures within the nucleus. (a) An active chromatin hub (ACH) is a structure that allows enhancers and promoters to come into close spatial proximity with each other (40). This structure has a high concentration of chromatin remodellers and PolII, which allows stable/high levels of transcription. Interactions between promoters and enhancers and represented by dashed lines. (b) The recruitment of genes and enhancers to a repressive chromatin hub (RCH) results in their downregulation (165). This structure potentially prevents enhancers from communicating with their cognate promoter by looping them out and preventing them from interacting. This structure may also restrict the amount of PolII from binding to gene promoters. (c and d) During development, genes in the Hox locus show a linear movement from a repressive chromatin structure to a region where they are expressed (166). This movement allows enhancers to interact with targets that were previously held in the repressive domain.
Mentions: In erythoid cells, where β-globin is expressed, these interactions form a compartment containing regulatory elements that has a high level of transcriptional activity (40). These chromatin structures depend on sequence-specific TFs bound to both the enhancer and promoter and thus can explain the specificity observed in enhancer:promoter interactions. Knock out of TFs responsible for regulating β-globin expression (EKLF and GATA-1) result in the loss of interactions between the gene and its enhancers, leading to loss of the overall hub-like structure (163,164). Interactions between regulatory elements separated by large genomic distances have been observed at high frequencies at other loci, leading to the proposition that chromatin looping generally results in the formation of hub-like structures. These active chromatin hubs (ACH) are responsible for bringing enhancers and promoters into close spatial proximity as well as providing an environment that is transcriptionally permissive (Figure 3a). The contents of the β-globin ACH changes during differentiation, with the ACH lacking certain elements in progenitor cells, which are found there later during differentiation (167). At the Myb locus during erythoid proliferation, intergenic enhancers, the Myb promoter and its first intron are brought together to form an ACH (168). The ACH leads to high concentrations of PolII and TFs being present around Myb. The first intron of this gene contains a site for regulating transcriptional elongation. Interactions between this element and distal enhancers lead to the generation of full-length transcripts. This structure is lost when cells terminally differentiate, coincident with the loss of expression of Myb and a reduction in TF binding at regulatory elements.Figure 3.

Bottom Line: The movement of enhancers and promoters in and out of higher-order chromatin structures within the nucleus are associated with changes in expression and histone modifications.However, the factors responsible for mediating these changes and determining enhancer:promoter specificity are still not completely known.In this review, we summarize what is known about the patterns of epigenetic and chromatin features characteristic of elements involved in long-range interactions.

View Article: PubMed Central - PubMed

Affiliation: MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London W12 0NN, UK, Institute of Clinical Sciences, Faculty of Medicine, Imperial College, London W12 0NN, UK and Department of Informatics, University of Bergen, Thromøhlensgate 55, N-5008 Bergen, Norway.

ABSTRACT
The precise regulation of gene transcription during metazoan development is controlled by a complex system of interactions between transcription factors, histone modifications and modifying enzymes and chromatin conformation. Developments in chromosome conformation capture technologies have revealed that interactions between regions of chromatin are pervasive and highly cell-type specific. The movement of enhancers and promoters in and out of higher-order chromatin structures within the nucleus are associated with changes in expression and histone modifications. However, the factors responsible for mediating these changes and determining enhancer:promoter specificity are still not completely known. In this review, we summarize what is known about the patterns of epigenetic and chromatin features characteristic of elements involved in long-range interactions. In addition, we review the insights into both local and global patterns of chromatin interactions that have been revealed by the latest experimental and computational methods.

Show MeSH