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Distinct epigenetic features of differentiation-regulated replication origins.

Smith OK, Kim R, Fu H, Martin MM, Lin CM, Utani K, Zhang Y, Marks AB, Lalande M, Chamberlain S, Libbrecht MW, Bouhassira EE, Ryan MC, Noble WS, Aladjem MI - Epigenetics Chromatin (2016)

Bottom Line: Consistent with a role of chromatin structure in determining origin activity, we found that cancer and non-cancer cells of similar lineages exhibited highly similar replication origin distributions.Surprisingly, our study revealed that DNase hypersensitivity, which often correlates with early replication at large-scale chromatin domains, did not emerge as a strong local determinant of origin activity.Instead, we found that two distinct sets of chromatin modifications exhibited strong local associations with two discrete groups of replication origins.

View Article: PubMed Central - PubMed

Affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.

ABSTRACT

Background: Eukaryotic genome duplication starts at discrete sequences (replication origins) that coordinate cell cycle progression, ensure genomic stability and modulate gene expression. Origins share some sequence features, but their activity also responds to changes in transcription and cellular differentiation status.

Results: To identify chromatin states and histone modifications that locally mark replication origins, we profiled origin distributions in eight human cell lines representing embryonic and differentiated cell types. Consistent with a role of chromatin structure in determining origin activity, we found that cancer and non-cancer cells of similar lineages exhibited highly similar replication origin distributions. Surprisingly, our study revealed that DNase hypersensitivity, which often correlates with early replication at large-scale chromatin domains, did not emerge as a strong local determinant of origin activity. Instead, we found that two distinct sets of chromatin modifications exhibited strong local associations with two discrete groups of replication origins. The first origin group consisted of about 40,000 regions that actively initiated replication in all cell types and preferentially colocalized with unmethylated CpGs and with the euchromatin markers, H3K4me3 and H3K9Ac. The second group included origins that were consistently active in cells of a single type or lineage and preferentially colocalized with the heterochromatin marker, H3K9me3. Shared origins replicated throughout the S-phase of the cell cycle, whereas cell-type-specific origins preferentially replicated during late S-phase.

Conclusions: These observations are in line with the hypothesis that differentiation-associated changes in chromatin and gene expression affect the activation of specific replication origins.

No MeSH data available.


Related in: MedlinePlus

Shared and cell-type-specific replication origins clustered by association with chromatin features. Alignment of origins with chromatin modifications was performed using ColoWeb [48] as exemplified in Fig. 4. Heat maps representing the extent of preferential association of origins with distinct chromatin modifications were clustered by chromatin modifications and cell lines. The extent of association between origins and each modification is color coded, with deeper red color representing higher mean-centered AMI values and blue representing lower values. Shared and cell-type-specific replication origins clustered separately and displayed distinct associations with chromatin modifications
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Fig6: Shared and cell-type-specific replication origins clustered by association with chromatin features. Alignment of origins with chromatin modifications was performed using ColoWeb [48] as exemplified in Fig. 4. Heat maps representing the extent of preferential association of origins with distinct chromatin modifications were clustered by chromatin modifications and cell lines. The extent of association between origins and each modification is color coded, with deeper red color representing higher mean-centered AMI values and blue representing lower values. Shared and cell-type-specific replication origins clustered separately and displayed distinct associations with chromatin modifications

Mentions: We next asked whether the association of histone modifications with replication origins was similar for shared and cell-type-specific origins. Shared origins associated strongly with the euchromatin markers H3K4me3, H3K9Ac and unmethylated CpG islands (Fig. 6) and weakly with methylated CpG islands, H3K9me3 and DNase hypersensitivity. Cell-type-specific origins exhibited stronger colocalization with the heterochromatin marker, H3K9me3, when compared with shared origins (Fig. 6). Cell-type-specific origins exhibited intermediate levels of colocalization with all other chromatin modifications analyzed. H3K27Ac exhibited similar colocalization with cell-type-specific and shared origins. Shared and cell-type-specific origins from EB and K562 cells (both of the myeloid lineage) clustered together, suggesting that replication origins from cells of the same lineage exhibit similar patterns.Fig. 6


Distinct epigenetic features of differentiation-regulated replication origins.

Smith OK, Kim R, Fu H, Martin MM, Lin CM, Utani K, Zhang Y, Marks AB, Lalande M, Chamberlain S, Libbrecht MW, Bouhassira EE, Ryan MC, Noble WS, Aladjem MI - Epigenetics Chromatin (2016)

Shared and cell-type-specific replication origins clustered by association with chromatin features. Alignment of origins with chromatin modifications was performed using ColoWeb [48] as exemplified in Fig. 4. Heat maps representing the extent of preferential association of origins with distinct chromatin modifications were clustered by chromatin modifications and cell lines. The extent of association between origins and each modification is color coded, with deeper red color representing higher mean-centered AMI values and blue representing lower values. Shared and cell-type-specific replication origins clustered separately and displayed distinct associations with chromatin modifications
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4862150&req=5

Fig6: Shared and cell-type-specific replication origins clustered by association with chromatin features. Alignment of origins with chromatin modifications was performed using ColoWeb [48] as exemplified in Fig. 4. Heat maps representing the extent of preferential association of origins with distinct chromatin modifications were clustered by chromatin modifications and cell lines. The extent of association between origins and each modification is color coded, with deeper red color representing higher mean-centered AMI values and blue representing lower values. Shared and cell-type-specific replication origins clustered separately and displayed distinct associations with chromatin modifications
Mentions: We next asked whether the association of histone modifications with replication origins was similar for shared and cell-type-specific origins. Shared origins associated strongly with the euchromatin markers H3K4me3, H3K9Ac and unmethylated CpG islands (Fig. 6) and weakly with methylated CpG islands, H3K9me3 and DNase hypersensitivity. Cell-type-specific origins exhibited stronger colocalization with the heterochromatin marker, H3K9me3, when compared with shared origins (Fig. 6). Cell-type-specific origins exhibited intermediate levels of colocalization with all other chromatin modifications analyzed. H3K27Ac exhibited similar colocalization with cell-type-specific and shared origins. Shared and cell-type-specific origins from EB and K562 cells (both of the myeloid lineage) clustered together, suggesting that replication origins from cells of the same lineage exhibit similar patterns.Fig. 6

Bottom Line: Consistent with a role of chromatin structure in determining origin activity, we found that cancer and non-cancer cells of similar lineages exhibited highly similar replication origin distributions.Surprisingly, our study revealed that DNase hypersensitivity, which often correlates with early replication at large-scale chromatin domains, did not emerge as a strong local determinant of origin activity.Instead, we found that two distinct sets of chromatin modifications exhibited strong local associations with two discrete groups of replication origins.

View Article: PubMed Central - PubMed

Affiliation: DNA Replication Group, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA.

ABSTRACT

Background: Eukaryotic genome duplication starts at discrete sequences (replication origins) that coordinate cell cycle progression, ensure genomic stability and modulate gene expression. Origins share some sequence features, but their activity also responds to changes in transcription and cellular differentiation status.

Results: To identify chromatin states and histone modifications that locally mark replication origins, we profiled origin distributions in eight human cell lines representing embryonic and differentiated cell types. Consistent with a role of chromatin structure in determining origin activity, we found that cancer and non-cancer cells of similar lineages exhibited highly similar replication origin distributions. Surprisingly, our study revealed that DNase hypersensitivity, which often correlates with early replication at large-scale chromatin domains, did not emerge as a strong local determinant of origin activity. Instead, we found that two distinct sets of chromatin modifications exhibited strong local associations with two discrete groups of replication origins. The first origin group consisted of about 40,000 regions that actively initiated replication in all cell types and preferentially colocalized with unmethylated CpGs and with the euchromatin markers, H3K4me3 and H3K9Ac. The second group included origins that were consistently active in cells of a single type or lineage and preferentially colocalized with the heterochromatin marker, H3K9me3. Shared origins replicated throughout the S-phase of the cell cycle, whereas cell-type-specific origins preferentially replicated during late S-phase.

Conclusions: These observations are in line with the hypothesis that differentiation-associated changes in chromatin and gene expression affect the activation of specific replication origins.

No MeSH data available.


Related in: MedlinePlus