Limits...
Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array.

Slieker RC, Bos SD, Goeman JJ, Bovée JV, Talens RP, van der Breggen R, Suchiman HE, Lameijer EW, Putter H, van den Akker EB, Zhang Y, Jukema JW, Slagboom PE, Meulenbelt I, Heijmans BT - Epigenetics Chromatin (2013)

Bottom Line: Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation.Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons).We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. B.T.Heijmans@lumc.nl.

ABSTRACT

Background: DNA methylation has been recognized as a key mechanism in cell differentiation. Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation. We used a new algorithm to identify and annotate tissue-specific differentially methylated regions (tDMRs) from Illumina 450k chip data for four peripheral tissues (blood, saliva, buccal swabs and hair follicles) and six internal tissues (liver, muscle, pancreas, subcutaneous fat, omentum and spleen with matched blood samples).

Results: The majority of tDMRs, in both relative and absolute terms, occurred in CpG-poor regions. Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons). Only a minority of tDMRs mapped to gene-body CpG islands (13%) or CpG islands shores (25%) suggesting a less prominent role for these regions than indicated previously. Implementation of ENCODE annotations showed enrichment of tDMRs in DNase hypersensitive sites and transcription factor binding sites. Despite the predominance of tissue differences, inter-individual differences in DNA methylation in internal tissues were correlated with those for blood for a subset of CpG sites in a locus- and tissue-specific manner.

Conclusions: We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription. Furthermore, our data suggest the utility of creating an atlas cataloguing variably methylated regions in internal tissues that correlate to DNA methylation measured in easy accessible peripheral tissues.

No MeSH data available.


Related in: MedlinePlus

Enrichment of GO terms with nearest genes of tDMRs. Different colours represent the distinct major classes. Notice the difference in major classes between genes enriched with tDMRs that have a CGI or CGI flanking region and those which do not. When no CGI is present, tissue-specific genes are observed, while when there is a CGI present, the genes enriched with a tDMR are more often involved in embryonic developmental processes and gene regulation genes. Genes with a differentially methylated shelf overlapping with the proximal promoter, were associated with developmental -, housekeeping -, and tissue-specific GO terms. CGI, CpG island; GO, gene ontology; tDMR, tissue-specific differentially methylated region.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3750594&req=5

Figure 5: Enrichment of GO terms with nearest genes of tDMRs. Different colours represent the distinct major classes. Notice the difference in major classes between genes enriched with tDMRs that have a CGI or CGI flanking region and those which do not. When no CGI is present, tissue-specific genes are observed, while when there is a CGI present, the genes enriched with a tDMR are more often involved in embryonic developmental processes and gene regulation genes. Genes with a differentially methylated shelf overlapping with the proximal promoter, were associated with developmental -, housekeeping -, and tissue-specific GO terms. CGI, CpG island; GO, gene ontology; tDMR, tissue-specific differentially methylated region.

Mentions: tDMRs were mapped to their nearest gene and enrichment analysis of gene ontology (GO) terms was used to describe functional categories. Non-CGI proximal promoters harbouring a tDMR were found to be involved in regulating tissue-specific processes reinforcing our previous observations of this class of tDMRs (Figure 5). In contrast, CGI proximal promoters harbouring a tDMR were largely associated with embryonic development processes. CGI shore proximal promoters with a tDMR were associated with similar processes as CGI proximal promoters with a tDMR, whereas CGI-shelf proximal promoters with a tDMR resembled non-CGI proximal promoters with a tDMR. The functional annotations of other tDMRs classes are given in Additional file 13: Figure S8.


Identification and systematic annotation of tissue-specific differentially methylated regions using the Illumina 450k array.

Slieker RC, Bos SD, Goeman JJ, Bovée JV, Talens RP, van der Breggen R, Suchiman HE, Lameijer EW, Putter H, van den Akker EB, Zhang Y, Jukema JW, Slagboom PE, Meulenbelt I, Heijmans BT - Epigenetics Chromatin (2013)

Enrichment of GO terms with nearest genes of tDMRs. Different colours represent the distinct major classes. Notice the difference in major classes between genes enriched with tDMRs that have a CGI or CGI flanking region and those which do not. When no CGI is present, tissue-specific genes are observed, while when there is a CGI present, the genes enriched with a tDMR are more often involved in embryonic developmental processes and gene regulation genes. Genes with a differentially methylated shelf overlapping with the proximal promoter, were associated with developmental -, housekeeping -, and tissue-specific GO terms. CGI, CpG island; GO, gene ontology; tDMR, tissue-specific differentially methylated region.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750594&req=5

Figure 5: Enrichment of GO terms with nearest genes of tDMRs. Different colours represent the distinct major classes. Notice the difference in major classes between genes enriched with tDMRs that have a CGI or CGI flanking region and those which do not. When no CGI is present, tissue-specific genes are observed, while when there is a CGI present, the genes enriched with a tDMR are more often involved in embryonic developmental processes and gene regulation genes. Genes with a differentially methylated shelf overlapping with the proximal promoter, were associated with developmental -, housekeeping -, and tissue-specific GO terms. CGI, CpG island; GO, gene ontology; tDMR, tissue-specific differentially methylated region.
Mentions: tDMRs were mapped to their nearest gene and enrichment analysis of gene ontology (GO) terms was used to describe functional categories. Non-CGI proximal promoters harbouring a tDMR were found to be involved in regulating tissue-specific processes reinforcing our previous observations of this class of tDMRs (Figure 5). In contrast, CGI proximal promoters harbouring a tDMR were largely associated with embryonic development processes. CGI shore proximal promoters with a tDMR were associated with similar processes as CGI proximal promoters with a tDMR, whereas CGI-shelf proximal promoters with a tDMR resembled non-CGI proximal promoters with a tDMR. The functional annotations of other tDMRs classes are given in Additional file 13: Figure S8.

Bottom Line: Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation.Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons).We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. B.T.Heijmans@lumc.nl.

ABSTRACT

Background: DNA methylation has been recognized as a key mechanism in cell differentiation. Various studies have compared tissues to characterize epigenetically regulated genomic regions, but due to differences in study design and focus there still is no consensus as to the annotation of genomic regions predominantly involved in tissue-specific methylation. We used a new algorithm to identify and annotate tissue-specific differentially methylated regions (tDMRs) from Illumina 450k chip data for four peripheral tissues (blood, saliva, buccal swabs and hair follicles) and six internal tissues (liver, muscle, pancreas, subcutaneous fat, omentum and spleen with matched blood samples).

Results: The majority of tDMRs, in both relative and absolute terms, occurred in CpG-poor regions. Further analysis revealed that these regions were associated with alternative transcription events (alternative first exons, mutually exclusive exons and cassette exons). Only a minority of tDMRs mapped to gene-body CpG islands (13%) or CpG islands shores (25%) suggesting a less prominent role for these regions than indicated previously. Implementation of ENCODE annotations showed enrichment of tDMRs in DNase hypersensitive sites and transcription factor binding sites. Despite the predominance of tissue differences, inter-individual differences in DNA methylation in internal tissues were correlated with those for blood for a subset of CpG sites in a locus- and tissue-specific manner.

Conclusions: We conclude that tDMRs preferentially occur in CpG-poor regions and are associated with alternative transcription. Furthermore, our data suggest the utility of creating an atlas cataloguing variably methylated regions in internal tissues that correlate to DNA methylation measured in easy accessible peripheral tissues.

No MeSH data available.


Related in: MedlinePlus