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Discovery of cell-type specific regulatory elements in the human genome using differential chromatin modification analysis.

Chen C, Zhang S, Zhang XS - Nucleic Acids Res. (2013)

Bottom Line: We found cell-type-specific elements unique to each cell type investigated.These unique features show significant cell-type-specific biological relevance and tend to be located within functional regulatory elements.These results demonstrate the power of a differential comparative epigenomic strategy in deciphering the human genome and characterizing cell specificity.

View Article: PubMed Central - PubMed

Affiliation: National Center for Mathematics and Interdisciplinary Sciences, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, China.

ABSTRACT
Chromatin modifications have been comprehensively illustrated to play important roles in gene regulation and cell diversity in recent years. Given the rapid accumulation of genome-wide chromatin modification maps across multiple cell types, there is an urgent need for computational methods to analyze multiple maps to reveal combinatorial modification patterns and define functional DNA elements, especially those are specific to cell types or tissues. In this current study, we developed a computational method using differential chromatin modification analysis (dCMA) to identify cell-type-specific genomic regions with distinctive chromatin modifications. We then apply this method to a public data set with modification profiles of nine marks for nine cell types to evaluate its effectiveness. We found cell-type-specific elements unique to each cell type investigated. These unique features show significant cell-type-specific biological relevance and tend to be located within functional regulatory elements. These results demonstrate the power of a differential comparative epigenomic strategy in deciphering the human genome and characterizing cell specificity.

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Relationship between CSREs and various genomic features. (A) The distribution of CSREs in six different genomic regions, including promoter, 5′ UTR, 3′ UTR, exon, intron and intergenic regions. (B) The fold enrichments of the CSREs in the six different genomic regions. (C) Box plot of the distance between the intergenic CSREs and the nearest TSSs, compared with those of randomly generated ones. For each intergenic CSRE, the random one was an arbitrarily selected genomic element from the same chromosome with the same length. Then, the distances between the random regions to their nearest TSS were computed. (D) The normalized proportion of CSREs in each chromosome (1–22, X) in all cell types. (The bar of chromosome 22 in K562 was truncated to 0.03 for visualization, and its real number is 0.056) (E) Bar plot of the CV (defined as the ratio of the standard deviation to the mean) of normalized proportion of CSREs in each cell type.
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gkt712-F2: Relationship between CSREs and various genomic features. (A) The distribution of CSREs in six different genomic regions, including promoter, 5′ UTR, 3′ UTR, exon, intron and intergenic regions. (B) The fold enrichments of the CSREs in the six different genomic regions. (C) Box plot of the distance between the intergenic CSREs and the nearest TSSs, compared with those of randomly generated ones. For each intergenic CSRE, the random one was an arbitrarily selected genomic element from the same chromosome with the same length. Then, the distances between the random regions to their nearest TSS were computed. (D) The normalized proportion of CSREs in each chromosome (1–22, X) in all cell types. (The bar of chromosome 22 in K562 was truncated to 0.03 for visualization, and its real number is 0.056) (E) Bar plot of the CV (defined as the ratio of the standard deviation to the mean) of normalized proportion of CSREs in each cell type.

Mentions: We explored the relations between CSREs and various genomic features to illustrate their potential functional roles. The proportion of CSREs in different genomic regions varied across the cell types (Figure 2A). The CSREs were significantly enriched at well-known regulatory regions, such as promoters, 5′ and 3′ UTRs (, Fisher’s exact tests) (Figure 2B). Exon and intron regions were also enriched in CSREs, suggesting that part of a gene body may serve as regulatory elements, such as enhancers, for its own expression (31). The strong enrichments of CSREs in promoter regions (, Fisher’s exact tests) demonstrates underlying modifications acting in promoter regions play critical roles in regulating gene expression. In particular, CSREs in the promoter regions of H1 ES cells were substantially enriched when compared to those found in the other cell types. These results imply more promoter regions are under epigenetic regulation in embryonic stem cells. As discussed later in the text, many promoters in H1 ES are marked by H3K27me3, a repressive chromatin modification, but these regions are tuned in poised status. These characteristics are consistent with the unique cellular context of pluripotent cells.Figure 2.


Discovery of cell-type specific regulatory elements in the human genome using differential chromatin modification analysis.

Chen C, Zhang S, Zhang XS - Nucleic Acids Res. (2013)

Relationship between CSREs and various genomic features. (A) The distribution of CSREs in six different genomic regions, including promoter, 5′ UTR, 3′ UTR, exon, intron and intergenic regions. (B) The fold enrichments of the CSREs in the six different genomic regions. (C) Box plot of the distance between the intergenic CSREs and the nearest TSSs, compared with those of randomly generated ones. For each intergenic CSRE, the random one was an arbitrarily selected genomic element from the same chromosome with the same length. Then, the distances between the random regions to their nearest TSS were computed. (D) The normalized proportion of CSREs in each chromosome (1–22, X) in all cell types. (The bar of chromosome 22 in K562 was truncated to 0.03 for visualization, and its real number is 0.056) (E) Bar plot of the CV (defined as the ratio of the standard deviation to the mean) of normalized proportion of CSREs in each cell type.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3814353&req=5

gkt712-F2: Relationship between CSREs and various genomic features. (A) The distribution of CSREs in six different genomic regions, including promoter, 5′ UTR, 3′ UTR, exon, intron and intergenic regions. (B) The fold enrichments of the CSREs in the six different genomic regions. (C) Box plot of the distance between the intergenic CSREs and the nearest TSSs, compared with those of randomly generated ones. For each intergenic CSRE, the random one was an arbitrarily selected genomic element from the same chromosome with the same length. Then, the distances between the random regions to their nearest TSS were computed. (D) The normalized proportion of CSREs in each chromosome (1–22, X) in all cell types. (The bar of chromosome 22 in K562 was truncated to 0.03 for visualization, and its real number is 0.056) (E) Bar plot of the CV (defined as the ratio of the standard deviation to the mean) of normalized proportion of CSREs in each cell type.
Mentions: We explored the relations between CSREs and various genomic features to illustrate their potential functional roles. The proportion of CSREs in different genomic regions varied across the cell types (Figure 2A). The CSREs were significantly enriched at well-known regulatory regions, such as promoters, 5′ and 3′ UTRs (, Fisher’s exact tests) (Figure 2B). Exon and intron regions were also enriched in CSREs, suggesting that part of a gene body may serve as regulatory elements, such as enhancers, for its own expression (31). The strong enrichments of CSREs in promoter regions (, Fisher’s exact tests) demonstrates underlying modifications acting in promoter regions play critical roles in regulating gene expression. In particular, CSREs in the promoter regions of H1 ES cells were substantially enriched when compared to those found in the other cell types. These results imply more promoter regions are under epigenetic regulation in embryonic stem cells. As discussed later in the text, many promoters in H1 ES are marked by H3K27me3, a repressive chromatin modification, but these regions are tuned in poised status. These characteristics are consistent with the unique cellular context of pluripotent cells.Figure 2.

Bottom Line: We found cell-type-specific elements unique to each cell type investigated.These unique features show significant cell-type-specific biological relevance and tend to be located within functional regulatory elements.These results demonstrate the power of a differential comparative epigenomic strategy in deciphering the human genome and characterizing cell specificity.

View Article: PubMed Central - PubMed

Affiliation: National Center for Mathematics and Interdisciplinary Sciences, Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing 100190, China.

ABSTRACT
Chromatin modifications have been comprehensively illustrated to play important roles in gene regulation and cell diversity in recent years. Given the rapid accumulation of genome-wide chromatin modification maps across multiple cell types, there is an urgent need for computational methods to analyze multiple maps to reveal combinatorial modification patterns and define functional DNA elements, especially those are specific to cell types or tissues. In this current study, we developed a computational method using differential chromatin modification analysis (dCMA) to identify cell-type-specific genomic regions with distinctive chromatin modifications. We then apply this method to a public data set with modification profiles of nine marks for nine cell types to evaluate its effectiveness. We found cell-type-specific elements unique to each cell type investigated. These unique features show significant cell-type-specific biological relevance and tend to be located within functional regulatory elements. These results demonstrate the power of a differential comparative epigenomic strategy in deciphering the human genome and characterizing cell specificity.

Show MeSH
Related in: MedlinePlus