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. 2012 Oct 26;13:566.
doi: 10.1186/1471-2164-13-566.

Euchromatin Islands in Large Heterochromatin Domains Are Enriched for CTCF Binding and Differentially DNA-methylated Regions

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Free PMC article

Euchromatin Islands in Large Heterochromatin Domains Are Enriched for CTCF Binding and Differentially DNA-methylated Regions

Bo Wen et al. BMC Genomics. .
Free PMC article

Abstract

Background: The organization of higher order chromatin is an emerging epigenetic mechanism for understanding development and disease. We and others have previously observed dynamic changes during differentiation and oncogenesis in large heterochromatin domains such as Large Organized Chromatin K (lysine) modifications (LOCKs), of histone H3 lysine-9 dimethylation (H3K9me2) or other repressive histone posttranslational modifications. The microstructure of these regions has not previously been explored.

Results: We analyzed the genome-wide distribution of H3K9me2 in two human pluripotent stem cell lines and three differentiated cells lines. We identified > 2,500 small regions with very low H3K9me2 signals in the body of LOCKs, which were termed as euchromatin islands (EIs). EIs are 6.5-fold enriched for DNase I Hypersensitive Sites and 8-fold enriched for the binding of CTCF, the major organizer of higher-order chromatin. Furthermore, EIs are 2-6 fold enriched for differentially DNA-methylated regions associated with tissue types (T-DMRs), reprogramming (R-DMRs) and cancer (C-DMRs). Gene ontology (GO) analysis suggests that EI-associated genes are functionally related to organ system development, cell adhesion and cell differentiation.

Conclusions: We identify the existence of EIs as a finer layer of epigenomic architecture within large heterochromatin domains. Their enrichment for CTCF sites and DNAse hypersensitive sites, as well as association with DMRs, suggest that EIs play an important role in normal epigenomic architecture and its disruption in disease.

Figures

Figure 1
Figure 1
Global pattern of H3K9me2 in human pluripotent and differentiated cells.A) A representative region that shows LOCKs in differentiated cells (HA, HAEC and HPF) but not PSCs (H1 and ADA-38). Shown are H3K9me2 signals of ChIP-chip experiments in a ~500 kb long region containing WSCD2 gene. Positive and negative log2 (ChIP/Input) rations are shown in blue and red, respectively. B) qPCR validation of ChIP-chip data. By comparing four cell lines in 23 regions (Figure S1), enrichments (log2 ChIP/Input) measured by ChIP-chip (Y axis) and ChIP-qPCR (X axis) are highly correlated (R2 = 0.87).
Figure 2
Figure 2
Euchromatin islands (EIs) in LOCKs overlap CTCF interacting regions and DNase hypersensitive sites (DHSs). H3K9me2 log ratios of HAEC are shown on the top track. CTCF binding regions and DHSs of HUVEC are denoted as light blue and orange bars, respectively. EIs are small regions with strong negative signals within the body of LOCKs. A) Shown is a 3 Mb long region (top) containing CHD11 genes (zoomed-in view on the bottom), a member of the cadherin gene family. CFCF interacting regions and DHSs are highly depleted in the H3K9me2 blocks (LOCKS), but overlap the EI located near the TSS of CDH11 gene. B) Additional examples of EIs near GP2 and PDILT genes.
Figure 3
Figure 3
EIs are enriched for differential methylation regions (DMRs). The H3K9me2 signals of HAEC and HPF are compared with regions of T-DMRs (pink bars). Regions of CHARM array are denoted by green bars. EIs (red dips) clearly overlap T-DMRs near the TSSs of NOS1 (A), XYLT1 (B) and HS3HT1 (C).
Figure 4
Figure 4
Expression of genes associated with EIs. We compared expression levels for genes with TSS at different regions. Expression values are RPKM (read per kb per million reads) for lung fibroblast IMR90 [7]. A) boxplot of expression level of genes with TSS 1) overlapping EIs; 2) overlapping LOCKs but not EIs; and 3) not overlapping EIs. B) Relationship between H3K36me3/H3K27me3 and expression of EI associated genes.
Figure 5
Figure 5
Cell type specific EIs.A) The Venn diagram shows overlaps of EIs among three differentiated cell lines (HA, HAEC and HPF). B-C) Shown are examples of EIs which differ among cell types. The annotation of tracks is the same as in Figures 2 and 3. An EI is found near the 5’ end of the myocardin gene (MYOCD) in HA and HPF but not in HAEC. An EI is found in the TSS of the Down syndrome cell adhesion molecule gene (DSCAM) specifically in HA but not in other two cell types (C).

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