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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

Timing of replication initiation in shared and cell-type-specific origins. Groups of a EB shared, b EB cell-type-specific, c K562 shared and d K562 cell-type-specific replication origins were stratified according to replication time. Replicating quintiles were created from BED files based on TimEX replication timing data for the EB cells [51] and Repli-seq for the K562 cell line [62]. The frequency of replication initiation in the first, third and fifth quintiles was plotted for genomic regions flanking replication origins. The histogram x axis extends 5-kb upstream and 5-kb downstream from the center of shared or cell-type-specific replication origins. The y axis represents the number of peaks shared among the indicated samples. Data are summarized in the histogram (e). Bar graph depicting the percent of shared (left) and cell-type-specific (right) origins found in each replication timing period. Shared replication origins exhibited a slight preference for early replication, whereas cell-type-specific replication origins were enriched in late timing stages
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Fig8: Timing of replication initiation in shared and cell-type-specific origins. Groups of a EB shared, b EB cell-type-specific, c K562 shared and d K562 cell-type-specific replication origins were stratified according to replication time. Replicating quintiles were created from BED files based on TimEX replication timing data for the EB cells [51] and Repli-seq for the K562 cell line [62]. The frequency of replication initiation in the first, third and fifth quintiles was plotted for genomic regions flanking replication origins. The histogram x axis extends 5-kb upstream and 5-kb downstream from the center of shared or cell-type-specific replication origins. The y axis represents the number of peaks shared among the indicated samples. Data are summarized in the histogram (e). Bar graph depicting the percent of shared (left) and cell-type-specific (right) origins found in each replication timing period. Shared replication origins exhibited a slight preference for early replication, whereas cell-type-specific replication origins were enriched in late timing stages

Mentions: To determine whether shared and cell-type-specific replication origins were activated at distinct replication times, we separated the origins from EB cells into fractions (first, third and fifth quintiles—see “Methods” section for details) stratified by the timing of DNA replication initiation [51] and determined the proportion of shared or cell-type-specific origins at each time period (Additional file 1: Table S5; Fig. 8). Shared replication origins replicated preferentially in early and middle S-phase whereas cell-type-specific origins replicated most frequently in the late replicating fraction. For example, 46.2 % of EB cell-type-specific origins replicated during the final stage of S-phase (vs. 5.4 and 15 % for early and middle S-phase, respectively) (Fig. 8b, e; Additional file 1: Table S5). Similar results were obtained for K562 origins (Fig. 8c, d). These observations indicated that shared replication origins were not restricted temporally, whereas cell-type-specific origins preferentially replicated during late S-phase.Fig. 8


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)

Timing of replication initiation in shared and cell-type-specific origins. Groups of a EB shared, b EB cell-type-specific, c K562 shared and d K562 cell-type-specific replication origins were stratified according to replication time. Replicating quintiles were created from BED files based on TimEX replication timing data for the EB cells [51] and Repli-seq for the K562 cell line [62]. The frequency of replication initiation in the first, third and fifth quintiles was plotted for genomic regions flanking replication origins. The histogram x axis extends 5-kb upstream and 5-kb downstream from the center of shared or cell-type-specific replication origins. The y axis represents the number of peaks shared among the indicated samples. Data are summarized in the histogram (e). Bar graph depicting the percent of shared (left) and cell-type-specific (right) origins found in each replication timing period. Shared replication origins exhibited a slight preference for early replication, whereas cell-type-specific replication origins were enriched in late timing stages
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig8: Timing of replication initiation in shared and cell-type-specific origins. Groups of a EB shared, b EB cell-type-specific, c K562 shared and d K562 cell-type-specific replication origins were stratified according to replication time. Replicating quintiles were created from BED files based on TimEX replication timing data for the EB cells [51] and Repli-seq for the K562 cell line [62]. The frequency of replication initiation in the first, third and fifth quintiles was plotted for genomic regions flanking replication origins. The histogram x axis extends 5-kb upstream and 5-kb downstream from the center of shared or cell-type-specific replication origins. The y axis represents the number of peaks shared among the indicated samples. Data are summarized in the histogram (e). Bar graph depicting the percent of shared (left) and cell-type-specific (right) origins found in each replication timing period. Shared replication origins exhibited a slight preference for early replication, whereas cell-type-specific replication origins were enriched in late timing stages
Mentions: To determine whether shared and cell-type-specific replication origins were activated at distinct replication times, we separated the origins from EB cells into fractions (first, third and fifth quintiles—see “Methods” section for details) stratified by the timing of DNA replication initiation [51] and determined the proportion of shared or cell-type-specific origins at each time period (Additional file 1: Table S5; Fig. 8). Shared replication origins replicated preferentially in early and middle S-phase whereas cell-type-specific origins replicated most frequently in the late replicating fraction. For example, 46.2 % of EB cell-type-specific origins replicated during the final stage of S-phase (vs. 5.4 and 15 % for early and middle S-phase, respectively) (Fig. 8b, e; Additional file 1: Table S5). Similar results were obtained for K562 origins (Fig. 8c, d). These observations indicated that shared replication origins were not restricted temporally, whereas cell-type-specific origins preferentially replicated during late S-phase.Fig. 8

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