SUMOylation fine-tunes the transcriptional activity of endothelial HEY1 in the regulation of angiogenesis [HUVEC RNA-seq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE241150 | GEO | 2024/01/10
REPOSITORIES: GEO
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Project description:To validate the results in primary endothelial cells including HUVECs and HMVECs, the effect of HEY1 SUMOylation on angiogenic functions was examined in MLECs isolated form Hey1 iEC-KO HEY1-WT/3KR iEC-KI mice.
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Project description:Our previous results from RNA-seq and IP-MS together suggest that SUMOylation may be critical for the DNA-binding capability of HEY1 to enhance its transcriptional repressive activity. To confirm our speculation, we conducted ChIP assays in HUVECs.
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Project description:Reversible HEY1 SUMOylation is a molecular mechanism that coordinates endothelial angiogenic signaling and angiogenesis, both in physiological and pathological milieus, by fine tuning the transcriptional activity of HEY1. Specifically, S UMOylation facilitates the formation of the HEY1 transcriptional complex and enhances its DNA binding capability in endothelial cells.
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Project description:Sumoylation is emerging as a post-translation modification important for chromosome duplication and stability. The origin recognition complex (ORC), which directs DNA replication initiation by loading the MCM replicative helicases onto origins, is sumoylated in both yeast and human cells. However, the biological consequences of ORC sumoylation are largely unclear. Here we report the effects of hyper- and hypo-sumoylation of yeast ORC using multiple approaches. We show that ORC hyper-sumoylation preferentially reduces the activity of a subset of early origins, while Orc2 hypo-sumoylation has an opposing effect. Mechanistically, ORC hyper-sumoylation leads to reduced MCM loading in vitro and diminished MCM chromatin association in vivo. The importance of an appropriate level of ORC sumoylation is suggested by the data that either hyper- or hypo-sumoylation of ORC results in genome instability and a dependence on other genome maintenance factors for cell fitness. Thus, yeast ORC sumoylation status needs to be fine-tuned to achieve optimal origin activity control and genome stability.
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Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation, typical to human mesenchymal chondrosarcoma. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses indicated frequent inclusion of the RUNX DNA consensus sequences within HEY1-NCOA2-binding peaks. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. This interaction promotes repression of Runx2 target genes such as Adamts4 and Mmp13 to suppress chondrocytic differentiation and cell growth of tumors, and treatment with the HDAC inhibitor Panobinostat abrogates the repression activity of HEY1-NCOA2 and Runx2 to inhibit tumor growth both in vitro and in vivo. These results demonstrate that HEY1-NCOA2 expression induces malignant transformation of chondrogenic progenitors by modulating the RUNX2-regulated transcriptional program. We used microarrays to detail the global program of gene expression in mouse mesenchymal chondrosarcoma
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Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation, typical to human mesenchymal chondrosarcoma. Chromatin immunoprecipitation sequencing (ChIP-seq) analyses indicated frequent inclusion of the RUNX DNA consensus sequences within HEY1-NCOA2-binding peaks. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. This interaction promotes repression of Runx2 target genes such as Adamts4 and Mmp13 to suppress chondrocytic differentiation and cell growth of tumors, and treatment with the HDAC inhibitor Panobinostat abrogates the repression activity of HEY1-NCOA2 and Runx2 to inhibit tumor growth both in vitro and in vivo. These results demonstrate that HEY1-NCOA2 expression induces malignant transformation of chondrogenic progenitors by modulating the RUNX2-regulated transcriptional program.
2023-09-11 | GSE163585 | GEO
Project description:Mesenchymal chondrosarcoma is a high-grade malignant neoplasm characterized by biphasic growth of poorly differentiated small round cells and well differentiated cartilage. Mesenchymal chondrosarcoma affects adolescents and young adults, and the HEY1-NCOA2 fusion gene is causally associated with most cases. Here we generate a mouse model for mesenchymal chondrosarcoma by introducing HEY1-NCOA2 into mouse embryonic chondrogenic progenitors (eSZ) followed by subcutaneous transplantation into nude mice. HEY1-NCOA2 expression in eSZ cells successfully induced subcutaneous tumors in 68.9% of recipients, showing biphasic morphologies and expression of Sox9, a master regulator of chondrogenic differentiation. Chromatin immunoprecipitation sequencing analyses indicated frequent association between HEY1-NCOA2-binding peaks and active enhancers. Runx2 that is important for differentiation and proliferation of the chondrocytic lineage is invariably expressed in mouse mesenchymal chondrosarcoma, and interaction between HEY1-NCOA2 and Runx2 is observed using NCOA2 C-terminal domains. Whereas Runx2 knockout resulted in significant delay in tumor onset, aggressive growth of immature small round cells was induced. Treatment with the HDAC inhibitor panobinostat suppressed tumor growth both in vitro and in vivo, abrogating expression of genes downstream of HEY1-NCOA2 and Runx2. Thus, HEY1-NCOA2 expression induces malignant transformation by modulating the transcriptional program in chondrogenic differentiation.
2023-09-11 | GSE198662 | GEO
Project description:Mesenchymal chondrosarcoma is a rare and often aggressive cancer that accounts for 2-10% of all chondrosarcomas. Genetically, this tumor is characterized by the recurrent HEY1-NCOA2 fusion. However, the oncogenic function of HEY1-NCOA2 fusion in mesenchymal chondrosarcoma remains to be elucidated. We stably transduced HEK293 as well as iPSC-derived mesenchymal stem cells (MSCs) with inducible- expression HEY1, NCOA2 and HEY1-NCOA2 construct, respectively. Using the stably transduced cell lines, we investigated the intracellular localization of HEY1-NCOA2 fusion protein and performed genome-wide chromatin Immunoprecipitation sequencing (ChIP-seq) and expression profiling (RNA-seq) to identify HEY1-NCOA2-dependent transcriptional regulation. In this study, HEY1-NCOA2 fusion protein was found to be localized to the nucleus, like wild-type HEY1; and extreme similarity in genome-wide DNA-binding pattern between HEY1-NCOA2 and wild-type HEY1 was observed. By gene expression profiling, HEY1-NCOA2-expression (MSC-HN+), HEY1-expression (MSC-HEY1+) and NCOA2-expression (MSC-NCOA2+) iPSC-MSCs can be robustly separated, and the combined differential gene expression (DGE) analysis and Gene Set Enrichment Analysis (GSEA) revealed that genes downregulated by HEY1 were positively enriched in MSC-HN+ versus control. Functional classification of HEY1-NCOA2 upregulated genes according to KEGG networks highlighted various pathways related to promoting cell proliferation in cancer, such as cell cycle pathway, Hedgehog and WNT signaling as well as PI3K-Akt signaling pathways. Indeed, MSC-HN+ cells displayed significantly accelerated proliferation and a significant increase in cell cycle transit when compared with control cells. In 3D spheroidal growth model, we also observed both accelerated cell proliferation and distinct morphological features of the MSC-HN+ cells in contrast to the control cells. Our data provide functional evidence that HEY1-NCOA2 fusion protein preferentially binds to DNA regions that are originally occupied by the wild-type HEY1 transcription factor, and the expression of some HEY1 target genes as well as their related pathways, that are normally repressed by HEY1, are activated in the presence of HEY1-NCOA2 fusion protein.
2022-04-08 | GSE196002 | GEO
Project description:Mesenchymal chondrosarcoma is a rare and often aggressive cancer that accounts for 2-10% of all chondrosarcomas. Genetically, this tumor is characterized by the recurrent HEY1-NCOA2 fusion. However, the oncogenic function of HEY1-NCOA2 fusion in mesenchymal chondrosarcoma remains to be elucidated. We stably transduced HEK293 as well as iPSC-derived mesenchymal stem cells (MSCs) with inducible- expression HEY1, NCOA2 and HEY1-NCOA2 construct, respectively. Using the stably transduced cell lines, we investigated the intracellular localization of HEY1-NCOA2 fusion protein and performed genome-wide chromatin Immunoprecipitation sequencing (ChIP-seq) and expression profiling (RNA-seq) to identify HEY1-NCOA2-dependent transcriptional regulation. In this study, HEY1-NCOA2 fusion protein was found to be localized to the nucleus, like wild-type HEY1; and extreme similarity in genome-wide DNA-binding pattern between HEY1-NCOA2 and wild-type HEY1 was observed. By gene expression profiling, HEY1-NCOA2-expression (MSC-HN+), HEY1-expression (MSC-HEY1+) and NCOA2-expression (MSC-NCOA2+) iPSC-MSCs can be robustly separated, and the combined differential gene expression (DGE) analysis and Gene Set Enrichment Analysis (GSEA) revealed that genes downregulated by HEY1 were positively enriched in MSC-HN+ versus control. Functional classification of HEY1-NCOA2 upregulated genes according to KEGG networks highlighted various pathways related to promoting cell proliferation in cancer, such as cell cycle pathway, Hedgehog and WNT signaling as well as PI3K-Akt signaling pathways. Indeed, MSC-HN+ cells displayed significantly accelerated proliferation and a significant increase in cell cycle transit when compared with control cells. In 3D spheroidal growth model, we also observed both accelerated cell proliferation and distinct morphological features of the MSC-HN+ cells in contrast to the control cells. Our data provide functional evidence that HEY1-NCOA2 fusion protein preferentially binds to DNA regions that are originally occupied by the wild-type HEY1 transcription factor, and the expression of some HEY1 target genes as well as their related pathways, that are normally repressed by HEY1, are activated in the presence of HEY1-NCOA2 fusion protein.
2022-04-08 | GSE196000 | GEO