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Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression.

Hua S, Kallen CB, Dhar R, Baquero MT, Mason CE, Russell BA, Shah PK, Liu J, Khramtsov A, Tretiakova MS, Krausz TN, Olopade OI, Rimm DL, White KP - Mol. Syst. Biol. (2008)

Bottom Line: Using RNA interference, selected ERalpha and c-MYC gene targets were knocked down to identify mediators of E2-stimulated cell proliferation.Tissue microarray screening revealed that high expression of an epigenetic factor, the E2-inducible histone variant H2A.Z, is significantly associated with lymph node metastasis and decreased breast cancer survival.Detection of H2A.Z levels independently increased the prognostic power of biomarkers currently in clinical use.

View Article: PubMed Central - PubMed

Affiliation: Joint Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.

ABSTRACT
We demonstrate an integrated approach to the study of a transcriptional regulatory cascade involved in the progression of breast cancer and we identify a protein associated with disease progression. Using chromatin immunoprecipitation and genome tiling arrays, whole genome mapping of transcription factor-binding sites was combined with gene expression profiling to identify genes involved in the proliferative response to estrogen (E2). Using RNA interference, selected ERalpha and c-MYC gene targets were knocked down to identify mediators of E2-stimulated cell proliferation. Tissue microarray screening revealed that high expression of an epigenetic factor, the E2-inducible histone variant H2A.Z, is significantly associated with lymph node metastasis and decreased breast cancer survival. Detection of H2A.Z levels independently increased the prognostic power of biomarkers currently in clinical use. This integrated approach has accelerated the identification of a molecule linked to breast cancer progression, has implications for diagnostic and therapeutic interventions, and can be applied to a wide range of cancers.

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Genomic distribution of ERα- and MYC-binding sites. The distributions of 1615 ERα- (A) and 311 MYC- (B) binding sites in E2-stimulated MCF7 cells relative to known genes. Where multiple genomic probes indicated a transcription factor-bound region, the center of each ERα- or MYC-binding region was designated as the bound position. Within annotated genes, binding sites were classified as follows: within 5′ untranslated regions (5′ UTR), within coding sequences (CDS), within 5′-most intron or the first intron, within other introns, and within 3′ untranslated regions (3′ UTR). ERα or MYC binding in intergenic regions was further classified based on the distance to the nearest annotated gene (0–10, 10–50, and >50 kb).
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f1: Genomic distribution of ERα- and MYC-binding sites. The distributions of 1615 ERα- (A) and 311 MYC- (B) binding sites in E2-stimulated MCF7 cells relative to known genes. Where multiple genomic probes indicated a transcription factor-bound region, the center of each ERα- or MYC-binding region was designated as the bound position. Within annotated genes, binding sites were classified as follows: within 5′ untranslated regions (5′ UTR), within coding sequences (CDS), within 5′-most intron or the first intron, within other introns, and within 3′ untranslated regions (3′ UTR). ERα or MYC binding in intergenic regions was further classified based on the distance to the nearest annotated gene (0–10, 10–50, and >50 kb).

Mentions: We identified a total of 1615 ERα-bound regions (P<1e−5) throughout the human genome (Supplementary Table 1). The distribution of ERα-binding regions ranged from proximal (<1 kb) to the nearest transcription start site (TSS) of a gene to over 500 kb from the closest TSS (Figure 1A). Similarly, we detected 311 MYC-bound regions across the human genome in MCF7 cells (Supplementary Table 2). The distribution of MYC-bound loci in relation to annotated TSSs is depicted in Figure 1B. A total of 62.4% of ERα-bound regions detected in our study were confirmed in an independently derived data set using similar methods (Carroll et al, 2006) (common sites are indicated in Supplementary Table 1).


Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression.

Hua S, Kallen CB, Dhar R, Baquero MT, Mason CE, Russell BA, Shah PK, Liu J, Khramtsov A, Tretiakova MS, Krausz TN, Olopade OI, Rimm DL, White KP - Mol. Syst. Biol. (2008)

Genomic distribution of ERα- and MYC-binding sites. The distributions of 1615 ERα- (A) and 311 MYC- (B) binding sites in E2-stimulated MCF7 cells relative to known genes. Where multiple genomic probes indicated a transcription factor-bound region, the center of each ERα- or MYC-binding region was designated as the bound position. Within annotated genes, binding sites were classified as follows: within 5′ untranslated regions (5′ UTR), within coding sequences (CDS), within 5′-most intron or the first intron, within other introns, and within 3′ untranslated regions (3′ UTR). ERα or MYC binding in intergenic regions was further classified based on the distance to the nearest annotated gene (0–10, 10–50, and >50 kb).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2394496&req=5

f1: Genomic distribution of ERα- and MYC-binding sites. The distributions of 1615 ERα- (A) and 311 MYC- (B) binding sites in E2-stimulated MCF7 cells relative to known genes. Where multiple genomic probes indicated a transcription factor-bound region, the center of each ERα- or MYC-binding region was designated as the bound position. Within annotated genes, binding sites were classified as follows: within 5′ untranslated regions (5′ UTR), within coding sequences (CDS), within 5′-most intron or the first intron, within other introns, and within 3′ untranslated regions (3′ UTR). ERα or MYC binding in intergenic regions was further classified based on the distance to the nearest annotated gene (0–10, 10–50, and >50 kb).
Mentions: We identified a total of 1615 ERα-bound regions (P<1e−5) throughout the human genome (Supplementary Table 1). The distribution of ERα-binding regions ranged from proximal (<1 kb) to the nearest transcription start site (TSS) of a gene to over 500 kb from the closest TSS (Figure 1A). Similarly, we detected 311 MYC-bound regions across the human genome in MCF7 cells (Supplementary Table 2). The distribution of MYC-bound loci in relation to annotated TSSs is depicted in Figure 1B. A total of 62.4% of ERα-bound regions detected in our study were confirmed in an independently derived data set using similar methods (Carroll et al, 2006) (common sites are indicated in Supplementary Table 1).

Bottom Line: Using RNA interference, selected ERalpha and c-MYC gene targets were knocked down to identify mediators of E2-stimulated cell proliferation.Tissue microarray screening revealed that high expression of an epigenetic factor, the E2-inducible histone variant H2A.Z, is significantly associated with lymph node metastasis and decreased breast cancer survival.Detection of H2A.Z levels independently increased the prognostic power of biomarkers currently in clinical use.

View Article: PubMed Central - PubMed

Affiliation: Joint Institute for Genomics and Systems Biology, The University of Chicago and Argonne National Laboratory, Chicago, IL, USA.

ABSTRACT
We demonstrate an integrated approach to the study of a transcriptional regulatory cascade involved in the progression of breast cancer and we identify a protein associated with disease progression. Using chromatin immunoprecipitation and genome tiling arrays, whole genome mapping of transcription factor-binding sites was combined with gene expression profiling to identify genes involved in the proliferative response to estrogen (E2). Using RNA interference, selected ERalpha and c-MYC gene targets were knocked down to identify mediators of E2-stimulated cell proliferation. Tissue microarray screening revealed that high expression of an epigenetic factor, the E2-inducible histone variant H2A.Z, is significantly associated with lymph node metastasis and decreased breast cancer survival. Detection of H2A.Z levels independently increased the prognostic power of biomarkers currently in clinical use. This integrated approach has accelerated the identification of a molecule linked to breast cancer progression, has implications for diagnostic and therapeutic interventions, and can be applied to a wide range of cancers.

Show MeSH
Related in: MedlinePlus