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Contrasting chromatin organization of CpG islands and exons in the human genome.

Choi JK - Genome Biol. (2010)

Bottom Line: CpG islands and nucleosome-free regions are both found in promoters.Exon-enrichment of DNA methylation was specifically found in spliced exons and in exons with weak splice sites.I also found that nucleosomes, DNA methylation, and H3K36me3 marked the exons of transcripts with low, medium, and high gene expression levels, respectively.

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Affiliation: Department of Biology and Brain Engineering, KAIST, 335 Gwahak-ro, Daejeon 305-701, Republic of Korea. jungkyoon@gmail.com

ABSTRACT

Background: CpG islands and nucleosome-free regions are both found in promoters. However, their association has never been studied. On the other hand, DNA methylation is absent in promoters but is enriched in gene bodies. Intragenic nucleosomes and their modifications have been recently associated with RNA splicing. Because the function of intragenic DNA methylation remains unclear, I explored the possibility of its involvement in splicing regulation.

Results: Here I show that CpG islands were associated not only with methylation-free promoters but also with nucleosome-free promoters. Nucleosome-free regions were observed only in promoters containing a CpG island. However, the DNA sequences of CpG islands predicted the opposite pattern, implying a limitation of sequence programs for the determination of nucleosome occupancy. In contrast to the methylation-and nucleosome-free states of CpG-island promoters, exons were densely methylated at CpGs and packaged into nucleosomes. Exon-enrichment of DNA methylation was specifically found in spliced exons and in exons with weak splice sites. The enrichment patterns were less pronounced in initial exons and in non-coding exons, potentially reflecting a lower need for their splicing. I also found that nucleosomes, DNA methylation, and H3K36me3 marked the exons of transcripts with low, medium, and high gene expression levels, respectively.

Conclusions: Human promoters containing a CpG island tend to remain nucleosome-free as well as methylation-free. In contrast, exons demonstrate a high degree of methylation and nucleosome occupancy. Exonic DNA methylation seems to function together with exonic nucleosomes and H3K36me3 for the proper splicing of transcripts with different expression levels.

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Nucleosome organization of promoter CGIs. (a-c) Nucleosome patterns upstream, inside and downstream of the CGI (from left to right) based on (a) in vivo nucleosome occupancy for human T cells [5] measured as normalized read count (NRC; see Materials and methods), (b) sequence prediction of nucleosome occupancy [15], and (c) DNA bending propensity. (d,e) Nucleosome patterns surrounding the transcription start site (TSS) based on (d) in vivo nucleosome occupancy for human T cells [5] measured as the NRC and (e) sequence prediction of nucleosome occupancy [15].
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Figure 1: Nucleosome organization of promoter CGIs. (a-c) Nucleosome patterns upstream, inside and downstream of the CGI (from left to right) based on (a) in vivo nucleosome occupancy for human T cells [5] measured as normalized read count (NRC; see Materials and methods), (b) sequence prediction of nucleosome occupancy [15], and (c) DNA bending propensity. (d,e) Nucleosome patterns surrounding the transcription start site (TSS) based on (d) in vivo nucleosome occupancy for human T cells [5] measured as the NRC and (e) sequence prediction of nucleosome occupancy [15].

Mentions: Expectedly, the in vivo nucleosome occupancy within the CGI is remarkably low compared to that in the flanking regions (Figure 1a). Open chromatin can be identified by DNase I hypersensitivity experiments. I used the whole-genome data of DNase I hypersensitivity sites [18] to assess their enrichment in CGIs (see Materials and methods). The fraction of the human genome that harbors these sites was compared with that of the CGIs that overlap these sites, producing an odds ratio of 14. This means that open chromatin is 14-fold more likely to be found in CGIs than in the other genomic regions.


Contrasting chromatin organization of CpG islands and exons in the human genome.

Choi JK - Genome Biol. (2010)

Nucleosome organization of promoter CGIs. (a-c) Nucleosome patterns upstream, inside and downstream of the CGI (from left to right) based on (a) in vivo nucleosome occupancy for human T cells [5] measured as normalized read count (NRC; see Materials and methods), (b) sequence prediction of nucleosome occupancy [15], and (c) DNA bending propensity. (d,e) Nucleosome patterns surrounding the transcription start site (TSS) based on (d) in vivo nucleosome occupancy for human T cells [5] measured as the NRC and (e) sequence prediction of nucleosome occupancy [15].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2926781&req=5

Figure 1: Nucleosome organization of promoter CGIs. (a-c) Nucleosome patterns upstream, inside and downstream of the CGI (from left to right) based on (a) in vivo nucleosome occupancy for human T cells [5] measured as normalized read count (NRC; see Materials and methods), (b) sequence prediction of nucleosome occupancy [15], and (c) DNA bending propensity. (d,e) Nucleosome patterns surrounding the transcription start site (TSS) based on (d) in vivo nucleosome occupancy for human T cells [5] measured as the NRC and (e) sequence prediction of nucleosome occupancy [15].
Mentions: Expectedly, the in vivo nucleosome occupancy within the CGI is remarkably low compared to that in the flanking regions (Figure 1a). Open chromatin can be identified by DNase I hypersensitivity experiments. I used the whole-genome data of DNase I hypersensitivity sites [18] to assess their enrichment in CGIs (see Materials and methods). The fraction of the human genome that harbors these sites was compared with that of the CGIs that overlap these sites, producing an odds ratio of 14. This means that open chromatin is 14-fold more likely to be found in CGIs than in the other genomic regions.

Bottom Line: CpG islands and nucleosome-free regions are both found in promoters.Exon-enrichment of DNA methylation was specifically found in spliced exons and in exons with weak splice sites.I also found that nucleosomes, DNA methylation, and H3K36me3 marked the exons of transcripts with low, medium, and high gene expression levels, respectively.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology and Brain Engineering, KAIST, 335 Gwahak-ro, Daejeon 305-701, Republic of Korea. jungkyoon@gmail.com

ABSTRACT

Background: CpG islands and nucleosome-free regions are both found in promoters. However, their association has never been studied. On the other hand, DNA methylation is absent in promoters but is enriched in gene bodies. Intragenic nucleosomes and their modifications have been recently associated with RNA splicing. Because the function of intragenic DNA methylation remains unclear, I explored the possibility of its involvement in splicing regulation.

Results: Here I show that CpG islands were associated not only with methylation-free promoters but also with nucleosome-free promoters. Nucleosome-free regions were observed only in promoters containing a CpG island. However, the DNA sequences of CpG islands predicted the opposite pattern, implying a limitation of sequence programs for the determination of nucleosome occupancy. In contrast to the methylation-and nucleosome-free states of CpG-island promoters, exons were densely methylated at CpGs and packaged into nucleosomes. Exon-enrichment of DNA methylation was specifically found in spliced exons and in exons with weak splice sites. The enrichment patterns were less pronounced in initial exons and in non-coding exons, potentially reflecting a lower need for their splicing. I also found that nucleosomes, DNA methylation, and H3K36me3 marked the exons of transcripts with low, medium, and high gene expression levels, respectively.

Conclusions: Human promoters containing a CpG island tend to remain nucleosome-free as well as methylation-free. In contrast, exons demonstrate a high degree of methylation and nucleosome occupancy. Exonic DNA methylation seems to function together with exonic nucleosomes and H3K36me3 for the proper splicing of transcripts with different expression levels.

Show MeSH