TRPS1 drives heterochromatic origin refiring and cancer genome evolution [copy number]
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ABSTRACT:
PROVIDER: PRJNA559389 | ENA |
REPOSITORIES: ENA
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Project description:The molecular etiology underlying TRPS1 loss-of-function in tricho-rhino-phalangeal syndrome (TRPS) remains to be understood. Intriguingly, TRPS1 is also bioinformatically postulated as a breast cancer driver. We report here that TRPS1 is prevalently amplified in breast cancer and promotes breast carcinogenesis. We showed that the tumorigenic potential of TRPS1 is derived from its nucleation of the replication machinery and its enforced replication of H3K9me3-marked heterochromatic regions. During early stage of genome duplication, TRPS1 encourages chromatin loading of the anaphase-promoting complex (APC/C) and subsequent degradation of Geminin, an inhibitor for the assembly of the pre-replication complex, leading to uncontrolled refiring of the heterochromatic replication origins. Overexpression of wild-type but not TRPS-associated loss-of-function mutants of TRPS1 is sufficient to drive genome amplification that mimics the genomic alterations in cancer, and TRPS1-evoked aberrant genome dynamically evolves to confer therapeutic resistance to a broad spectrum of treatment compounds. Together, these results link TRPS1 to heterochromatin replication, highlighting the sufficiency of a single oncogene to drive cancer genome evolution.
2022-08-08 | GSE135598 | GEO
Project description:The molecular etiology underlying TRPS1 loss-of-function in tricho-rhino-phalangeal syndrome (TRPS) remains to be understood. Intriguingly, TRPS1 is also bioinformatically postulated as a breast cancer driver. We report here that TRPS1 is prevalently amplified in breast cancer and promotes breast carcinogenesis. We showed that the tumorigenic potential of TRPS1 is derived from its nucleation of the replication machinery and its enforced replication of H3K9me3-marked heterochromatic regions. During early stage of genome duplication, TRPS1 encourages chromatin loading of the anaphase-promoting complex (APC/C) and subsequent degradation of Geminin, an inhibitor for the assembly of the pre-replication complex, leading to uncontrolled refiring of the heterochromatic replication origins. Overexpression of wild-type but not TRPS-associated loss-of-function mutants of TRPS1 is sufficient to drive genome amplification that mimics the genomic alterations in cancer, and TRPS1-evoked aberrant genome dynamically evolves to confer therapeutic resistance to a broad spectrum of treatment compounds. Together, these results link TRPS1 to heterochromatin replication, highlighting the sufficiency of a single oncogene to drive cancer genome evolution.
2021-08-16 | GSE118643 | GEO
Project description:TRPS1 drives heterochromatic origin refiring and cancer genome evolution
| PRJNA486389 | ENA
Project description:Copy number variation in an invasive fish of hybrid origin
| PRJNA359761 | ENA
Project description:Mutations in TRPS1 cause trichorhinophalangeal syndrome types I and III, which are characterized by sparse scalp hair in addition to craniofacial and skeletal abnormalities. Trps1 is a vertebrate transcription factor containing nine zinc-finger domains, including a GATA-type zinc finger through which it binds DNA. Mice in which the GATA domain of Trps1 has been deleted (Trps1∆gt/∆gt) have a reduced number of pelage follicles and lack vibrissae follicles postnatally. To identify the transcriptional targets of Trps1 in the developing vibrissa follicle, we performed microarray hybridization analysis comparing expression patterns in the whisker pads of wild-type versus Trps1∆gt/∆gt embryos. We identified a number of transcription factors and Wnt inhibitors among transcripts downregulated in the mutant embryos, and several extracellular matrix proteins there were upregulated in the mutant samples. Whole whisker pads were dissected from E12.5 embryos and total RNA was isolated using the RNeasy Mini Kit (Qiagen). Triplicate RNA samples from three independent embryos of each genotype were amplified and labeled for hybridization to Affymetrix GeneChip MOE430A microarrays using Affymetrix reagents and protocols. The data output was analyzed using GeneSpring GX 10.0 commercial software (Agilent Technologies). P-values were calculated using an unpaired t-test. Expression values with a p-value less than or equal to 0.05 and a fold difference of at least 1.5 relative to wild-type baseline expression levels were considered significant.
2011-12-22 | E-GEOD-33766 | biostudies-arrayexpress
Project description:TRPS1 was recently identified as a radiation marker in breast cancer. In order to characterise the molecular phenotype that is associated with TRPS1 we knocked out the gene in two radiation-transformed breast cell lines.
2017-10-01 | E-MTAB-6008 | biostudies-arrayexpress
Project description:Many human cancers present as multi-focal lesions. Understanding the clonal origin of multi-focal cancers is of both etiological and clinical importance. The molecular basis of multi-focal prostate cancer has previously been explored using only a limited number of isolated markers and, although independent origin is widely believed, the clonal origin of multi-focal prostate cancer is still debatable. We attempted to address clonal origin using a genome-wide copy-number analysis of individual cancer and high-grade prostatic intraepithelial neoplasia (HGPIN) lesions. Using Affymetrix array 6.0 copy-number analysis, we compared the genomic changes detected in 54 individual cancer and HGPIN lesions, isolated from 20 clinically localized prostate cancer cases. Identical genomic copy-number changes, shared by all same-case cancer foci, were detected in all 16 informative multi-tumor cases. In addition, both HGPIN lesions in the two multi-HGPIN cases available shared identical genomic changes. Commonly known genomic alterations, including losses at 6q15, 8p21.3-8p21.2, 10q23.2-10q23.31, 13q21.31-13q21.32, 16q22.3, 16q23.2-16q23.3 and 21q22.2-21q22.3 regions and gain of 8q24.3 were the most frequently detected changes in this multi-focal prostate cancer study, occurring in all same-case foci in at least one case. Microarray data were confirmed by fluorescence in situ hybridization in selected foci. Our high-resolution genome-wide copy-number data suggest that many multi-focal cases derive from a single prostate cancer precursor clone and that this precursor may give rise to separate HGPIN foci, which through clonal expansion may progress to multi-focal invasive prostate cancer. These findings, which demonstrate the monoclonal origin of multi-focal prostate cancer, should significantly enhance our understanding of prostate carcinogenesis and potentially improve clinical management of the disease.
2011-12-31 | GSE29569 | GEO
Project description:Many human cancers present as multi-focal lesions. Understanding the clonal origin of multi-focal cancers is of both etiological and clinical importance. The molecular basis of multi-focal prostate cancer has previously been explored using only a limited number of isolated markers and, although independent origin is widely believed, the clonal origin of multi-focal prostate cancer is still debatable. We attempted to address clonal origin using a genome-wide copy-number analysis of individual cancer and high-grade prostatic intraepithelial neoplasia (HGPIN) lesions. Using Affymetrix array 6.0 copy-number analysis, we compared the genomic changes detected in 54 individual cancer and HGPIN lesions, isolated from 20 clinically localized prostate cancer cases. Identical genomic copy-number changes, shared by all same-case cancer foci, were detected in all 16 informative multi-tumor cases. In addition, both HGPIN lesions in the two multi-HGPIN cases available shared identical genomic changes. Commonly known genomic alterations, including losses at 6q15, 8p21.3-8p21.2, 10q23.2-10q23.31, 13q21.31-13q21.32, 16q22.3, 16q23.2-16q23.3 and 21q22.2-21q22.3 regions and gain of 8q24.3 were the most frequently detected changes in this multi-focal prostate cancer study, occurring in all same-case foci in at least one case. Microarray data were confirmed by fluorescence in situ hybridization in selected foci. Our high-resolution genome-wide copy-number data suggest that many multi-focal cases derive from a single prostate cancer precursor clone and that this precursor may give rise to separate HGPIN foci, which through clonal expansion may progress to multi-focal invasive prostate cancer. These findings, which demonstrate the monoclonal origin of multi-focal prostate cancer, should significantly enhance our understanding of prostate carcinogenesis and potentially improve clinical management of the disease. Copy number analysis of Affymetrix SNP 6.0 array was performed for a total of 48 cancer and HGPIN lesions from 18 prostate cancer cases. All samples have case-matched normal controls. PL = high grade PIN from left side, PR = high grade PIN from right side, PM = high grade PIN from middle of the tissue, TL = tumour from left side, TR = tumour from right side.
2011-12-31 | E-GEOD-29569 | biostudies-arrayexpress
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.
2024-05-24 | GSE243509 | GEO
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.
2024-05-24 | GSE243504 | GEO