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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

Association of subsets of EB replication origins with annotated genomic domains. Subsets of EB replication origins (all origins, shared origins and cell-type-specific origins) were stratified based on replication timing and investigated for their association with K562 genomic domains using SAGA analysis [56]. For each subgroup, the extent of enrichment for a particular domain is indicated on the scale of color bar. Repressive domains include constitutive heterochromatin (CON), facultative heterochromatin (FAC) and quiescent domains (QUI). Active domains include broad expression domains (BRD) and specific expression domains (SPC). The groups designated “early,” “late” and “middle” represent all origins stratified by replication time (during S-phase). The “none” group corresponds to all non-origin positions
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Fig7: Association of subsets of EB replication origins with annotated genomic domains. Subsets of EB replication origins (all origins, shared origins and cell-type-specific origins) were stratified based on replication timing and investigated for their association with K562 genomic domains using SAGA analysis [56]. For each subgroup, the extent of enrichment for a particular domain is indicated on the scale of color bar. Repressive domains include constitutive heterochromatin (CON), facultative heterochromatin (FAC) and quiescent domains (QUI). Active domains include broad expression domains (BRD) and specific expression domains (SPC). The groups designated “early,” “late” and “middle” represent all origins stratified by replication time (during S-phase). The “none” group corresponds to all non-origin positions

Mentions: Replication origins identified in the EB cells were divided into two sets: shared and cell-type-specific origins as well as origins replicating during early, middle and late S-phase (Fig. 7) [51]. Chromatin domains used for the SAGA analyses were identified in K562 cells, representing the erythroid lineage. In agreement with our colocalization analyses, SAGA found that all replication origins were enriched in SPC and depleted in CON and QUI domains. SAGA confirmed that shared replication origins were associated with active chromatin domains, whereas cell-type-specific origins showed no strong enrichment within any domain. Early replicating origins were enriched in SPC domains and were depleted from CON domains, whereas origins activated during middle and late S-phase both showed some enrichment in FAC domains.Fig. 7


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)

Association of subsets of EB replication origins with annotated genomic domains. Subsets of EB replication origins (all origins, shared origins and cell-type-specific origins) were stratified based on replication timing and investigated for their association with K562 genomic domains using SAGA analysis [56]. For each subgroup, the extent of enrichment for a particular domain is indicated on the scale of color bar. Repressive domains include constitutive heterochromatin (CON), facultative heterochromatin (FAC) and quiescent domains (QUI). Active domains include broad expression domains (BRD) and specific expression domains (SPC). The groups designated “early,” “late” and “middle” represent all origins stratified by replication time (during S-phase). The “none” group corresponds to all non-origin positions
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig7: Association of subsets of EB replication origins with annotated genomic domains. Subsets of EB replication origins (all origins, shared origins and cell-type-specific origins) were stratified based on replication timing and investigated for their association with K562 genomic domains using SAGA analysis [56]. For each subgroup, the extent of enrichment for a particular domain is indicated on the scale of color bar. Repressive domains include constitutive heterochromatin (CON), facultative heterochromatin (FAC) and quiescent domains (QUI). Active domains include broad expression domains (BRD) and specific expression domains (SPC). The groups designated “early,” “late” and “middle” represent all origins stratified by replication time (during S-phase). The “none” group corresponds to all non-origin positions
Mentions: Replication origins identified in the EB cells were divided into two sets: shared and cell-type-specific origins as well as origins replicating during early, middle and late S-phase (Fig. 7) [51]. Chromatin domains used for the SAGA analyses were identified in K562 cells, representing the erythroid lineage. In agreement with our colocalization analyses, SAGA found that all replication origins were enriched in SPC and depleted in CON and QUI domains. SAGA confirmed that shared replication origins were associated with active chromatin domains, whereas cell-type-specific origins showed no strong enrichment within any domain. Early replicating origins were enriched in SPC domains and were depleted from CON domains, whereas origins activated during middle and late S-phase both showed some enrichment in FAC domains.Fig. 7

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