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

ABSTRACT: Estrogen receptor α (ERα) is key player in the progression of breast cancer. ERα 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 ERα binding sites (ERBS) identified from the recent ChIA-PET of ERα. More importantly, we demonstrate that AP-2γ (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 ERα binding events. Furthermore, pertubation of AP-2γ expression disrupts ERα DNA binding, long-range chromatin interactions, and gene transcription. Using ChIP-seq, we show that AP-2γ and ERα 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-2γ 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-2γ and FoxA1. Together, our results suggest AP-2γ is an essential factor in ERα-mediated transcription, primarily working together with FoxA1 to facilitate ERα binding and long-range chromatin interactions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE23852 | GEO | 2011/06/03

SECONDARY ACCESSION(S): PRJNA142709

REPOSITORIES: GEO

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Activator protein-2γ is a critical determinant of estrogen receptor interactome formation and gene transcription in breast cancer [expression]

Project description:Estrogen receptor α (ERα) is key player in the progression of breast cancer. ERα 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 ERα binding sites (ERBS) identified from the recent ChIA-PET of ERα. More importantly, we demonstrate that AP-2γ (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 ERα binding events. Furthermore, pertubation of AP-2γ expression disrupts ERα DNA binding, long-range chromatin interactions, and gene transcription. Using ChIP-seq, we show that AP-2γ and ERα 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-2γ 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-2γ and FoxA1. Together, our results suggest AP-2γ is an essential factor in ERα-mediated transcription, primarily working together with FoxA1 to facilitate ERα binding and long-range chromatin interactions.

2011-06-02 | GSE26740 | GEO

Activator protein-2Î³ is a critical determinant of estrogen receptor interactome formation and gene transcription in breast cancer [expression]

Project description:Estrogen receptor Î± (ERÎ±) is key player in the progression of breast cancer. ERÎ± 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 ERÎ± binding sites (ERBS) identified from the recent ChIA-PET of ERÎ±. More importantly, we demonstrate that AP-2Î³ (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 ERÎ± binding events. Furthermore, pertubation of AP-2Î³ expression disrupts ERÎ± DNA binding, long-range chromatin interactions, and gene transcription. Using ChIP-seq, we show that AP-2Î³ and ERÎ± 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-2Î³ 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-2Î³ and FoxA1. Together, our results suggest AP-2Î³ is an essential factor in ERÎ±-mediated transcription, primarily working together with FoxA1 to facilitate ERÎ± binding and long-range chromatin interactions. Gene expression profiling of negative control (NC) and AP-2Î³ siRNA transfected MCF-7, with and without E2 (estradiol) stimulation using microarray.

2011-06-02 | E-GEOD-26740 | biostudies-arrayexpress

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

Project description: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.

2011-06-03 | E-GEOD-23852 | biostudies-arrayexpress

TRIM37 augments AP-2γ transcriptional activity and cellular localization via K63-linked polyubiquitination to drive breast cancer progression [ChIP-seq]

Project description:Using a proteomics approach, we identified the Tripartite Motif Containing 37 (TRIM37) as a novel transcriptional coactivator of AP-2γ. We demonstrate TRIM37 facilitates AP-2γ chromatin binding to regulate the AP-2γ mediated transcriptional program directly. We provide evidence that TRIM37 achieves this by stimulating K63-chain-linked polyubiquitination of AP-2γ, promoting protein localization from the cytoplasm to the nucleus. In clinical analyses, we find TRIM37 is upregulated in multiple breast cancer datasets, supporting our findings that TRIM37-AP-2γ interaction is essential for breast cancer tumor growth. Overall, our work revealed that TRIM37 is an oncogenic coactivator of AP-2γ in breast cancer and provides a novel therapeutic target for treating the disease.

2022-07-25 | GSE182546 | GEO

TRIM37 augments AP-2γ transcriptional activity and cellular localization via K63-linked polyubiquitination to drive breast cancer progression [RNA-seq]

2022-07-25 | GSE182545 | GEO

Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1 [EMSA-seq]

Project description:Pioneer factors (PFs) are a subset of transcription factors (TFs) that can bind to nucleosomal DNA and invade closed chromatin. Despite that nucleosomes do not present a strong barrier to PF binding, PF can only bind to a small fraction of motifs in the genome. The underlying mechanism of such binding selectivity is not well understood. Here, we design a high-throughput assay named Chromatin Immunoprecipitation over Integrated Synthetic Oligonucleotides (ChIP-ISO) to systematically dissect the sequence features affecting the binding specificity of a classic PF, FOXA1, in A549 human lung carcinoma cells. This method involves integrating thousands of synthetic sequences containing FOXA1 motifs into a fixed genomic locus, followed by FOXA1 chromatin immunoprecipitation (ChIP) and amplicon sequencing. We find that 1) FOXA1 binding is affected by motif strength and co-binding TFs AP-1 and CEBPB, with AP-1 playing a major role in promoting FOXA1 binding, 2) FOXA1 binding in vivo and in vitro are poorly correlated, and FOXA1 and AP-1 show binding cooperativity in vitro, 3) FoxA1’s binding specificity is mostly determined by the local sequences, whereas chromatin context, including heterochromatin marks, only plays a minor role, and 4) AP-1 is at least partially responsible for differential binding of FOXA1 in different cell types. Finally, neural network analysis shows that AP-1 and CEBPB motifs are predictive of FOXA1 ChIP-seq peaks in A549, but not in some other cell types. In summary, combining ChIP-ISO with in vitro and in silico analyses, our study provides insights into the genetic rules underlying PF binding specificity and reveals a mechanism for its regulation during cell differentiation.

2023-11-09 | GSE247431 | GEO

Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1 [RNA-seq]

2023-11-09 | GSE247414 | GEO

Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1 [ChIP-seq]

2023-11-09 | GSE247412 | GEO

Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1 [ChIP-ISO]

2023-11-09 | GSE247411 | GEO

AP-2γ is Required for Maintenance of Multipotent Mammary Stem Cells

Project description:Mammary gland ductal morphogenesis depends on the differentiation of mammary stem cells (MaSCs) into basal and luminal lineages. The AP-2γ transcription factor, encoded by Tfap2c, has a central role in mammary gland development but its effect in mammary lineages and specifically MaSCs is largely unknown. Herein, we utilized an inducible, conditional knockout of Tfap2c to elucidate the role of AP-2γ in maintenance and differentiation of MaSCs. Loss of AP-2γ in the basal epithelium profoundly altered the transcriptomes and decreased the number of cells within several clusters of mammary epithelial cells, including adult MaSCs and luminal progenitors. AP-2γ regulated the expression of genes known to be required for mammary development including Cebpb, Nfkbia, and Rspo1. As a result, AP-2γ-deficient mice exhibited repressed mammary gland ductal outgrowth and inhibition of regenerative capacity. The findings demonstrate that AP-2γ can regulate development of mammary gland structures potentially regulating maintenance and differentiation of multipotent MaSCs.

2020-12-30 | GSE143159 | GEO

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