Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Activator protein-2M-NM-3 is a critical determinant of estrogen receptor interactome formation and gene transcription in breast cancer [ChIP-Seq]

ABSTRACT: Estrogen receptor M-NM-1 (ERM-NM-1) is key player in the progression of breast cancer. ERM-NM-1 binds to DNA and mediates long-range chromatin interactions throughout the genome, but the underlying mechanism in this process is unclear. Here, we show that AP-2 motifs are highly enriched in the ERM-NM-1 binding sites (ERBS) identified from the recent ChIA-PET of ERM-NM-1. More importantly, we demonstrate that AP-2M-NM-3 (also known as TFAP2C), a member of the AP-2 family which has been implicated in breast cancer oncogenesis, is recruited to chromatin in a ligand-independent manner and co-localized with ERM-NM-1 binding events. Furthermore, pertubation of AP-2M-NM-3 expression disrupts ERM-NM-1 DNA binding, long-range chromatin interactions, and gene transcription. Using ChIP-seq, we show that AP-2M-NM-3 and ERM-NM-1 binding occurs in close proximity on a genome-wide scale. The majority of these shared genomic regions are also occupied by the pioneer factor, FoxA1. AP-2M-NM-3 is required for efficient FoxA1 binding and vice versa. Finally, we show that most ERBS associated with long-range chromatin interactions are co-localized with both AP-2M-NM-3 and FoxA1. Together, our results suggest AP-2M-NM-3 is an essential factor in ERM-NM-1-mediated transcription, primarily working together with FoxA1 to facilitate ERM-NM-1 binding and long-range chromatin interactions. Genome-wide binding analysis of AP-2M-NM-3 and FoxA1 in MCF-7 with and without E2 (estradiol) stimulation using ChIP-Seq.

ORGANISM(S): Homo sapiens

SUBMITTER: SI KEE TAN

PROVIDER: E-GEOD-23852 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

AP-2γ regulates oestrogen receptor-mediated long-range chromatin interaction and gene transcription.

Tan Si Kee SK Lin Zhen Hua ZH Chang Cheng Wei CW Varang Vipin V Chng Kern Rei KR Pan You Fu YF Yong Eu Leong EL Sung Wing Kin WK Cheung Edwin E

The EMBO journal 20110513 13

Oestrogen receptor α (ERα) is key player in the progression of breast cancer. Recently, the cistrome and interactome of ERα were mapped in breast cancer cells, revealing the importance of spatial organization in oestrogen-mediated transcription. However, the underlying mechanism of this process is unclear. Here, we show that ERα binding sites (ERBS) identified from the Chromatin Interaction Analysis-Paired End DiTag of ERα are enriched for AP-2 motifs. We demonstrate the transcription factor, AP ...[more]

PMID: 21572391

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Project description:The interplay between mitogenic and proinflammatory signaling pathways play key roles in determining the phenotypes and clinical outcomes of breast cancers. We have used global nuclear run-on coupled with deep sequencing to characterize the immediate transcriptional responses of MCF-7 breast cancer cells treated with estradiol, TNFM-NM-1, or both. In addition, we have integrated these data with chromatin immunoprecipitation coupled with deep sequencing for estrogen receptor alpha (ERM-NM-1), the pioneer factor FoxA1 and the p65 subunit of the NF-M-NM-:B transcription factor. Our results indicate extensive transcriptional interplay between these two signaling pathways, which is observed for a number of classical mitogenic and proinflammatory protein-coding genes. In addition, GRO-seq has allowed us to capture the transcriptional crosstalk at the genomic locations encoding for long non-coding RNAs, a poorly characterized class of RNAs which have been shown to play important roles in cancer outcomes. The synergistic and antagonistic interplay between estrogen and TNFM-NM-1 signaling at the gene level is also evident in the patterns of ERM-NM-1 and NF-M-NM-:B binding, which relocalize to new binding sites that are not occupied by either treatment alone. Interestingly, the chromatin accessibility of classical ERM-NM-1 binding sites is predetermined prior to estrogen treatment, whereas ERM-NM-1 binding sites gained upon co-treatment with TNFM-NM-1 require NF-M-NM-:B and FoxA1 to promote chromatin accessibility de novo. Our data suggest that TNFM-NM-1 signaling recruits FoxA1 and NF-M-NM-:B to latent ERM-NM-1 enhancer locations and directly impact ERM-NM-1 enhancer accessibility. Binding of ERM-NM-1 to latent enhancers upon co-treatment, results in increased enhancer transcription, target gene expression and altered cellular response. This provides a mechanistic framework for understanding the molecular basis for integration of mitogenic and proinflammatory signaling in breast cancer. Using GRO-seq and ChIP-seq (ER, FoxA1 and p65) to assay the molecular crosstalk of MCF-7 cells treated with E2, TNFM-NM-1 or both E2+TNFM-NM-1.

Project description:To advance understanding of mechanisms leading to biological and transcriptional endpoints related to estrogen action in the mouse uterus, we have mapped ERM-NM-1 and RNA polymerase II binding sites using chromatin immunoprecipitation (ChIP) followed by sequencing of enriched chromatin fragments (ChIP-seq). In the absence of hormone, 5184 ERM-NM-1 binding sites were apparent in the vehicle treated ovariectomized uterine chromatin, while 17240 were seen one hour after estrogen (E2) treatment, indicating that some sites are occupied by unliganded ERM-NM-1, and that ERM-NM-1 binding is increased by E2. Approximately 15% of the uterine ERM-NM-1 binding sites were adjacent to (<10 KB) annotated transcription start sites and many sites are found within genes or are found more than 100 KB distal from mapped genes; however, the density (sites per bp) of ERM-NM-1 binding sites is significantly greater adjacent to promoters. An increase in quantity of sites but no significant positional differences were seen between vehicle and E2 treated samples in the overall locations of ERM-NM-1 binding sites either distal from, adjacent to or within genes. Analysis of the PolII data revealed the presence of poised promoter proximal PolII on some highly upregulated genes. Additionally, co-recruitment of PolII and ERM-NM-1 to some distal enhancer regions was observed. A de novo motif analysis of sequences in the ERM-NM-1 bound chromatin confirmed that estrogen response elements (EREs) were significantly enriched. Interestingly, in areas of ERM-NM-1 binding without predicted ERE motifs, homeodomain transcription factor (Hox) binding motifs were significantly enriched. The integration of the ERM-NM-1 and PolII binding sites from our uterine ChIP-seq data with transcriptional responses revealed in our uterine microarrays has the potential to greatly enhance our understanding of mechanisms governing estrogen response in uterine and other estrogen target tissues. one sample each, vehicle ER-alpha ChIP seq,1 hour estradiol ER-alpha ChIP seq, vehicle RNA polymerase II ChIP seq,1 hour estradiol RNA polymerase II ChIP seq, input DNA

Dataset Information

Activator protein-2M-NM-3 is a critical determinant of estrogen receptor interactome formation and gene transcription in breast cancer [ChIP-Seq]

Publications

AP-2γ regulates oestrogen receptor-mediated long-range chromatin interaction and gene transcription.

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