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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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Illustration of two distinctive modification patterns revealed by CSREs: the BCR-ABL fusion gene and the INSIG1 gene. (A) The left two plots show the binary modification profiles of the two component genes that make up the BCR-ABL fusion gene in all nine cell types investigated. BCR and ABL gene are covered by one and five CSRE, respectively. Five red bottom lines indicate those five adjacent CSREs covering ABL gene. The top right two plots show the corresponding detailed modification patterns in K562, where the Philadelphia translocation results in the fusion gene. (B) The average intensity comparison of three marks before and after the BCR gene TSS. (C) Binary modification patterns of the CSRE encompassing the promoter region of the INSIG1 gene. (D) The dramatic loss of five active marks including H3K4me1/2/3, H3K27ac and H3K9ac in HepG2 (note that the heights of corresponding bars are almost zero). The modification intensity in the ‘others’ group was calculated based on the combination profiles of the other eight cell types.
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gkt712-F6: Illustration of two distinctive modification patterns revealed by CSREs: the BCR-ABL fusion gene and the INSIG1 gene. (A) The left two plots show the binary modification profiles of the two component genes that make up the BCR-ABL fusion gene in all nine cell types investigated. BCR and ABL gene are covered by one and five CSRE, respectively. Five red bottom lines indicate those five adjacent CSREs covering ABL gene. The top right two plots show the corresponding detailed modification patterns in K562, where the Philadelphia translocation results in the fusion gene. (B) The average intensity comparison of three marks before and after the BCR gene TSS. (C) Binary modification patterns of the CSRE encompassing the promoter region of the INSIG1 gene. (D) The dramatic loss of five active marks including H3K4me1/2/3, H3K27ac and H3K9ac in HepG2 (note that the heights of corresponding bars are almost zero). The modification intensity in the ‘others’ group was calculated based on the combination profiles of the other eight cell types.

Mentions: The first case study we will explore is known as the Philadelphia translocation. The Philadelphia translocation is a chromosome abnormality involving chromosomes 9 and 22, which results in an oncogenic fusion gene BCR-ABL, and is a hallmark of chronic myelogenous leukemia (41,42). In the erythrocytic leukemia cells (K562), both pieces of the BCR-ABL fusion gene (BCR on chromosomes 22 and ABL1 on chromosomes 9) contain CSREs, demonstrating distinctly different epigenetic profile from the other cell types (Figure 6A). Specifically, BCR contains a CSRE consisting of 766 200 bp bins and ABL1 contains five adjacent CSREs. We found three marks including H3K27me3, H3K36me3 and H3K20me1 have distinctive characteristics at these regions (Figure 6A and B). We observed that H3K27me3, a histone modification associated with Polycomb-repressed regions (43), appears upstream of the BCR transcriptional start site and downstream of the ABL1 transcriptional termination site; however, this modification is almost absent in both gene bodies. In contrast, H3K36me3, a histone modification related to transcribed regions (6), had strong signals across the gene body of both genes, exhibiting a mutually exclusive occupancy pattern to that of H3K27me3. These observations imply that there is precise epigenetic control on the transcriptional boundaries of this fusion gene. Another histone modification, H3K20me1, also related to transcribed gene regions (6), is present in the region ranging from upstream of BCR to downstream of ABL1; moreover, it does not demonstrate any exclusivity with H3K27me3 or H3K36me3, suggesting a different functional role. Finally, CTCF, H3K27ac and H3K9ac exhibit stronger signals across the BCR-ABL regions in K562 cells than those observed in the other cell types examined. These distinctive chromatin modification patterns highlight specialized epigenetic regulation of these two genes; any dysfunction in them may be directly related to transcription of the fusion gene.Figure 6.


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)

Illustration of two distinctive modification patterns revealed by CSREs: the BCR-ABL fusion gene and the INSIG1 gene. (A) The left two plots show the binary modification profiles of the two component genes that make up the BCR-ABL fusion gene in all nine cell types investigated. BCR and ABL gene are covered by one and five CSRE, respectively. Five red bottom lines indicate those five adjacent CSREs covering ABL gene. The top right two plots show the corresponding detailed modification patterns in K562, where the Philadelphia translocation results in the fusion gene. (B) The average intensity comparison of three marks before and after the BCR gene TSS. (C) Binary modification patterns of the CSRE encompassing the promoter region of the INSIG1 gene. (D) The dramatic loss of five active marks including H3K4me1/2/3, H3K27ac and H3K9ac in HepG2 (note that the heights of corresponding bars are almost zero). The modification intensity in the ‘others’ group was calculated based on the combination profiles of the other eight cell types.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3814353&req=5

gkt712-F6: Illustration of two distinctive modification patterns revealed by CSREs: the BCR-ABL fusion gene and the INSIG1 gene. (A) The left two plots show the binary modification profiles of the two component genes that make up the BCR-ABL fusion gene in all nine cell types investigated. BCR and ABL gene are covered by one and five CSRE, respectively. Five red bottom lines indicate those five adjacent CSREs covering ABL gene. The top right two plots show the corresponding detailed modification patterns in K562, where the Philadelphia translocation results in the fusion gene. (B) The average intensity comparison of three marks before and after the BCR gene TSS. (C) Binary modification patterns of the CSRE encompassing the promoter region of the INSIG1 gene. (D) The dramatic loss of five active marks including H3K4me1/2/3, H3K27ac and H3K9ac in HepG2 (note that the heights of corresponding bars are almost zero). The modification intensity in the ‘others’ group was calculated based on the combination profiles of the other eight cell types.
Mentions: The first case study we will explore is known as the Philadelphia translocation. The Philadelphia translocation is a chromosome abnormality involving chromosomes 9 and 22, which results in an oncogenic fusion gene BCR-ABL, and is a hallmark of chronic myelogenous leukemia (41,42). In the erythrocytic leukemia cells (K562), both pieces of the BCR-ABL fusion gene (BCR on chromosomes 22 and ABL1 on chromosomes 9) contain CSREs, demonstrating distinctly different epigenetic profile from the other cell types (Figure 6A). Specifically, BCR contains a CSRE consisting of 766 200 bp bins and ABL1 contains five adjacent CSREs. We found three marks including H3K27me3, H3K36me3 and H3K20me1 have distinctive characteristics at these regions (Figure 6A and B). We observed that H3K27me3, a histone modification associated with Polycomb-repressed regions (43), appears upstream of the BCR transcriptional start site and downstream of the ABL1 transcriptional termination site; however, this modification is almost absent in both gene bodies. In contrast, H3K36me3, a histone modification related to transcribed regions (6), had strong signals across the gene body of both genes, exhibiting a mutually exclusive occupancy pattern to that of H3K27me3. These observations imply that there is precise epigenetic control on the transcriptional boundaries of this fusion gene. Another histone modification, H3K20me1, also related to transcribed gene regions (6), is present in the region ranging from upstream of BCR to downstream of ABL1; moreover, it does not demonstrate any exclusivity with H3K27me3 or H3K36me3, suggesting a different functional role. Finally, CTCF, H3K27ac and H3K9ac exhibit stronger signals across the BCR-ABL regions in K562 cells than those observed in the other cell types examined. These distinctive chromatin modification patterns highlight specialized epigenetic regulation of these two genes; any dysfunction in them may be directly related to transcription of the fusion gene.Figure 6.

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