TRPS1 modulates chromatin accessibility to regulate estrogen receptor (ER) binding and ER target gene expression in luminal breast cancer cells (3 clone PRO-seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1055443 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27313900_1.fastq.gz | Fastqsanger.gz | |||
| SRR27313900_2.fastq.gz | Fastqsanger.gz | |||
| SRR27313901_1.fastq.gz | Fastqsanger.gz | |||
| SRR27313901_2.fastq.gz | Fastqsanger.gz | |||
| SRR27313902_1.fastq.gz | Fastqsanger.gz |
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Project description:Breast cancer is the most frequently diagnosed cancer in women. The most common subtype is luminal breast cancer, which is typically driven by estrogen receptor alpha (ER), a transcription factor (TF) that activates many genes required for proliferation. Multiple effective therapies target this pathway, but individuals often develop resistance. Thus, there is a need to identify additional targets that regulate ER activity and contribute to breast tumor progression. TRPS1 is a repressive GATA-family TF that is overexpressed in breast tumors. Common genetic variants in the TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. However, we do not know how TRPS1 regulates target genes to mediate these breast cancer patient and cellular outcomes. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over eighty percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes ER to redistribute in the genome. ER redistribution causes direct repression of ER targets and indirectly activates dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the activity of other TFs, both activating and repressing transcription of genes related to cancer cell fitness.
2023-12-21 | GSE251772 | GEO
Project description:Breast cancer is the most frequently diagnosed cancer in women. The most common subtype is luminal breast cancer, which is typically driven by the estrogen receptor alpha (ER), a transcription factor (TF) that activates many genes required for proliferation. Multiple effective therapies target this pathway, but individuals often develop resistance. Thus, there is a need to identify additional targets that regulate ER activity and contribute to breast tumor progression. TRPS1 is a repressive GATA-family TF that is overexpressed in breast tumors. Common genetic variants in the TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. However, we do not know how TRPS1 regulates target genes to mediate these breast cancer patient and cellular outcomes. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over eighty percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes ER to redistribute in the genome. ER redistribution causes direct repression of ER targets and indirectly activates dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the activity of other TFs, both activating and repressing transcription of genes related to cancer cell fitness.
2023-07-02 | GSE236172 | GEO
Project description:Breast cancer is the most frequently diagnosed cancer in women. The most common subtype is luminal breast cancer, which is typically driven by the estrogen receptor alpha (ER), a transcription factor (TF) that activates many genes required for proliferation. Multiple effective therapies target this pathway, but individuals often develop resistance. Thus, there is a need to identify additional targets that regulate ER activity and contribute to breast tumor progression. TRPS1 is a repressive GATA-family TF that is overexpressed in breast tumors. Common genetic variants in the TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. However, we do not know how TRPS1 regulates target genes to mediate these breast cancer patient and cellular outcomes. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over eighty percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes ER to redistribute in the genome. ER redistribution causes direct repression of ER targets and indirectly activates dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the activity of other TFs, both activating and repressing transcription of genes related to cancer cell fitness.
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Project description:Breast cancer is the most frequently diagnosed cancer in women. The most common subtype is luminal breast cancer, which is typically driven by the estrogen receptor alpha (ER), a transcription factor (TF) that activates many genes required for proliferation. Multiple effective therapies target this pathway, but individuals often develop resistance. Thus, there is a need to identify additional targets that regulate ER activity and contribute to breast tumor progression. TRPS1 is a repressive GATA-family TF that is overexpressed in breast tumors. Common genetic variants in the TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. However, we do not know how TRPS1 regulates target genes to mediate these breast cancer patient and cellular outcomes. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over eighty percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes ER to redistribute in the genome. ER redistribution causes direct repression of ER targets and indirectly activates dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the activity of other TFs, both activating and repressing transcription of genes related to cancer cell fitness.
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Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
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Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
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Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
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Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
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Project description:The GATA transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and sustains the initial branching of the mammary ducts at puberty as well as the lactogenic differentiation during pregnancy. Its function in the resting mammary gland however, remains unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy resting mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. we show that TRPS1 activity is critical to maintain a functional luminal progenitor compartment and that this involves the repression of the SRF/MRTF and the YAP/TAZ transcriptional program. Mechanistically, this repression involves Krt8-dependent RhoA modulation. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors which is intrinsically linked to mechanotransduction in the mammary gland. It also provides new insights into the oncogenic functions of TRPS1 since luminal progenitors are likely the cells of origin of many breast cancers.
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