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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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(a) The genomic regulatory block model of transcriptional regulation. Genes involved in the regulation of developmental processes are themselves regulated by enhancers located in a variety of locations, both upstream and downstream. Developmentally regulated genes tend to have CpG islands (CGIs) that overlap with its promoter and extend into the body of the gene. Genes with Type II and III promoters typically feature a broad TSS distribution, as detected by CAGE. (b) Regulatory elements within the genome can be identified by distinct patterns of histone modifications and TF binding. Promoters are enriched for H3K4me3, with active promoters showing evidence of PolII binding. The presence of the repressive mark at promoters and depletion of H3K4me3 is associated with inactive repressed promoters. Promoters having both H3K4me3 and H3K27me3 are termed bivalent promoters; they are repressed but poised for activation. Both poised and active enhancers are marked by the histone modification H3K4me1 and show depletion of H3K4me3. In addition, active enhancers are marked by H3K27ac and the binding of P300, whereas poised enhancers lack H3K27ac and may be marked by H3K27me3.
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gkt499-F1: (a) The genomic regulatory block model of transcriptional regulation. Genes involved in the regulation of developmental processes are themselves regulated by enhancers located in a variety of locations, both upstream and downstream. Developmentally regulated genes tend to have CpG islands (CGIs) that overlap with its promoter and extend into the body of the gene. Genes with Type II and III promoters typically feature a broad TSS distribution, as detected by CAGE. (b) Regulatory elements within the genome can be identified by distinct patterns of histone modifications and TF binding. Promoters are enriched for H3K4me3, with active promoters showing evidence of PolII binding. The presence of the repressive mark at promoters and depletion of H3K4me3 is associated with inactive repressed promoters. Promoters having both H3K4me3 and H3K27me3 are termed bivalent promoters; they are repressed but poised for activation. Both poised and active enhancers are marked by the histone modification H3K4me1 and show depletion of H3K4me3. In addition, active enhancers are marked by H3K27ac and the binding of P300, whereas poised enhancers lack H3K27ac and may be marked by H3K27me3.

Mentions: Long-range regulation imposes constraints on the organization of the genome (57) and its evolution (58). In Drosophila and vertebrates, developmental genes are associated with arrays of enhancers and CNEs (9,54). Maintaining the correct patterns of gene expression requires that regulatory elements are kept in cis with their target genes. This has led to the maintenance of large regions of conserved synteny over large evolutionary distances (9,54,59), referred to as genomic regulatory blocks (GRBs). These GRBs can extend over large distances and often span large-genomic regions of low-gene density, called gene deserts, or encompass one or more bystander genes in addition to the target gene (Figure 1). Misregulation of GRB target genes has been implicated in developmental disorders and abnormal phenotypes. Mutations in the gene deserts flanking GRB target genes [e.g. SOX9 (60) and PAX6 (49)] are involved in developmental disorders (61). More generally, mutations in distal regulatory elements have been implicated in a variety of diseases, including cancer (62), type II diabetes (63) and dyslexia (64). It is thought that variation within CNEs may have a role in a number of common human disorders (65), and it may help to explain why a large proportion of disease associated single-nucleotide polymorphisms identified using genome-wide association studies (GWAS) are located within non-coding regions (66,67).Figure 1.


Chromatin and epigenetic features of long-range gene regulation.

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

(a) The genomic regulatory block model of transcriptional regulation. Genes involved in the regulation of developmental processes are themselves regulated by enhancers located in a variety of locations, both upstream and downstream. Developmentally regulated genes tend to have CpG islands (CGIs) that overlap with its promoter and extend into the body of the gene. Genes with Type II and III promoters typically feature a broad TSS distribution, as detected by CAGE. (b) Regulatory elements within the genome can be identified by distinct patterns of histone modifications and TF binding. Promoters are enriched for H3K4me3, with active promoters showing evidence of PolII binding. The presence of the repressive mark at promoters and depletion of H3K4me3 is associated with inactive repressed promoters. Promoters having both H3K4me3 and H3K27me3 are termed bivalent promoters; they are repressed but poised for activation. Both poised and active enhancers are marked by the histone modification H3K4me1 and show depletion of H3K4me3. In addition, active enhancers are marked by H3K27ac and the binding of P300, whereas poised enhancers lack H3K27ac and may be marked by H3K27me3.
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Related In: Results  -  Collection

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gkt499-F1: (a) The genomic regulatory block model of transcriptional regulation. Genes involved in the regulation of developmental processes are themselves regulated by enhancers located in a variety of locations, both upstream and downstream. Developmentally regulated genes tend to have CpG islands (CGIs) that overlap with its promoter and extend into the body of the gene. Genes with Type II and III promoters typically feature a broad TSS distribution, as detected by CAGE. (b) Regulatory elements within the genome can be identified by distinct patterns of histone modifications and TF binding. Promoters are enriched for H3K4me3, with active promoters showing evidence of PolII binding. The presence of the repressive mark at promoters and depletion of H3K4me3 is associated with inactive repressed promoters. Promoters having both H3K4me3 and H3K27me3 are termed bivalent promoters; they are repressed but poised for activation. Both poised and active enhancers are marked by the histone modification H3K4me1 and show depletion of H3K4me3. In addition, active enhancers are marked by H3K27ac and the binding of P300, whereas poised enhancers lack H3K27ac and may be marked by H3K27me3.
Mentions: Long-range regulation imposes constraints on the organization of the genome (57) and its evolution (58). In Drosophila and vertebrates, developmental genes are associated with arrays of enhancers and CNEs (9,54). Maintaining the correct patterns of gene expression requires that regulatory elements are kept in cis with their target genes. This has led to the maintenance of large regions of conserved synteny over large evolutionary distances (9,54,59), referred to as genomic regulatory blocks (GRBs). These GRBs can extend over large distances and often span large-genomic regions of low-gene density, called gene deserts, or encompass one or more bystander genes in addition to the target gene (Figure 1). Misregulation of GRB target genes has been implicated in developmental disorders and abnormal phenotypes. Mutations in the gene deserts flanking GRB target genes [e.g. SOX9 (60) and PAX6 (49)] are involved in developmental disorders (61). More generally, mutations in distal regulatory elements have been implicated in a variety of diseases, including cancer (62), type II diabetes (63) and dyslexia (64). It is thought that variation within CNEs may have a role in a number of common human disorders (65), and it may help to explain why a large proportion of disease associated single-nucleotide polymorphisms identified using genome-wide association studies (GWAS) are located within non-coding regions (66,67).Figure 1.

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