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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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Targets of E2 signaling participate in epigenetic regulation. Targets of E2 signaling involved in epigenetic regulation of gene expression were observed. These chromatin factors include the components in Polycomb group (PcG) complexes, DNA methyltransferases and methyl-DNA-binding proteins, histone modifiers, histone chaperones, variant histones, and proteins maintaining higher-order chromatin structure. Gene expression changes upon E2 treatment are color-coded (log2-transformed fold changes). Genes for which ERα or MYC binding was detected (ChIP-chip sites) are indicated and the location of the binding site relative to the TSS is depicted (see color legend).
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f6: Targets of E2 signaling participate in epigenetic regulation. Targets of E2 signaling involved in epigenetic regulation of gene expression were observed. These chromatin factors include the components in Polycomb group (PcG) complexes, DNA methyltransferases and methyl-DNA-binding proteins, histone modifiers, histone chaperones, variant histones, and proteins maintaining higher-order chromatin structure. Gene expression changes upon E2 treatment are color-coded (log2-transformed fold changes). Genes for which ERα or MYC binding was detected (ChIP-chip sites) are indicated and the location of the binding site relative to the TSS is depicted (see color legend).

Mentions: Epigenetic alterations play critical roles in tumorigenesis and cancer progression (Lund and van Lohuizen, 2004; Feinberg et al, 2006). We identified targets of E2 involved in many aspects of epigenetic regulation (Figure 6). Members of the Polycomb group involved in transcriptional silencing, including EZH2 and EED, both components of the Polycomb repressive complex 2 (PRC2), were upregulated by E2 (Figure 6). In addition, E2 activated the expression of other genes associated with PRC2 activity, including HDAC2, DNMT1, and HMGB1. HDAC2 has been shown to interact with EED in vivo and DNMT1 can be recruited to target genes by interacting with EZH2. The Drosophila homologue of HMGB1, Dsp1, plays an essential role in recruiting Polycomb proteins to target chromatin. Although the specific targets of Polycomb complexes in breast epithelial cells are largely unknown, the overexpression of components associated with PRC2 by E2 is intriguing because high levels of EZH2 have been associated with increased cancer cell proliferation, tumor invasiveness, and poor prognosis in breast cancer (Kleer et al, 2003).


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)

Targets of E2 signaling participate in epigenetic regulation. Targets of E2 signaling involved in epigenetic regulation of gene expression were observed. These chromatin factors include the components in Polycomb group (PcG) complexes, DNA methyltransferases and methyl-DNA-binding proteins, histone modifiers, histone chaperones, variant histones, and proteins maintaining higher-order chromatin structure. Gene expression changes upon E2 treatment are color-coded (log2-transformed fold changes). Genes for which ERα or MYC binding was detected (ChIP-chip sites) are indicated and the location of the binding site relative to the TSS is depicted (see color legend).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Targets of E2 signaling participate in epigenetic regulation. Targets of E2 signaling involved in epigenetic regulation of gene expression were observed. These chromatin factors include the components in Polycomb group (PcG) complexes, DNA methyltransferases and methyl-DNA-binding proteins, histone modifiers, histone chaperones, variant histones, and proteins maintaining higher-order chromatin structure. Gene expression changes upon E2 treatment are color-coded (log2-transformed fold changes). Genes for which ERα or MYC binding was detected (ChIP-chip sites) are indicated and the location of the binding site relative to the TSS is depicted (see color legend).
Mentions: Epigenetic alterations play critical roles in tumorigenesis and cancer progression (Lund and van Lohuizen, 2004; Feinberg et al, 2006). We identified targets of E2 involved in many aspects of epigenetic regulation (Figure 6). Members of the Polycomb group involved in transcriptional silencing, including EZH2 and EED, both components of the Polycomb repressive complex 2 (PRC2), were upregulated by E2 (Figure 6). In addition, E2 activated the expression of other genes associated with PRC2 activity, including HDAC2, DNMT1, and HMGB1. HDAC2 has been shown to interact with EED in vivo and DNMT1 can be recruited to target genes by interacting with EZH2. The Drosophila homologue of HMGB1, Dsp1, plays an essential role in recruiting Polycomb proteins to target chromatin. Although the specific targets of Polycomb complexes in breast epithelial cells are largely unknown, the overexpression of components associated with PRC2 by E2 is intriguing because high levels of EZH2 have been associated with increased cancer cell proliferation, tumor invasiveness, and poor prognosis in breast cancer (Kleer et al, 2003).

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