Effect of overexpression of HMGA2 in human chondrosarcoma SW1353 cell line overexpression and control cells.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE289237 | GEO | 2026/05/27
REPOSITORIES: GEO
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Project description:Overexpression of high mobility group AT-hook 2 (HMGA2) associated with truncations of its 3’ untranslated region (UTR) with let-7 micro RNA-complementary sequences have been identified in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we generated transgenic mice (∆Hmga2 mice) with a 3’UTR-trncated Hmga2 cDNA that overexpress Hmga2 mRNA and protein in hematopoietic organs. ∆Hmga2 mice showed proliferative hematopoiesis that mimicked a myeloproliferative neoplasm (MPN)-like phenotype with increased numbers of all lineages of peripheral blood cells, hypercellular bone marrow (BM), splenomegaly with extramedullary erythropoiesis, and erythropoietin-independent erythroid colony formation compared to wild-type mice. ∆Hmga2 BM-derived cells took over most of hematopoiesis in competitive repopulations during serial BM transplants. When we bred mice with circulating PNH cells (Piga- mice) with ∆Hmga2 mice, the lack of GPI-linked proteins did not add an additional clonal advantage to the ∆Hmga2+ cells. In summary, our results showed that the overexpression of a 3’UTR-truncated Hmga2 leads to a proliferative hematopoiesis with clonal advantage, which may explain clonal expansion in PNH or MPN at the level of HSC.
2011-02-06 | GSE24071 | GEO
Project description:Overexpression of high mobility group AT-hook 2 (HMGA2) associated with truncations of its 3’ untranslated region (UTR) with let-7 micro RNA-complementary sequences have been identified in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we generated transgenic mice (∆Hmga2 mice) with a 3’UTR-trncated Hmga2 cDNA that overexpress Hmga2 mRNA and protein in hematopoietic organs. ∆Hmga2 mice showed proliferative hematopoiesis that mimicked a myeloproliferative neoplasm (MPN)-like phenotype with increased numbers of all lineages of peripheral blood cells, hypercellular bone marrow (BM), splenomegaly with extramedullary erythropoiesis, and erythropoietin-independent erythroid colony formation compared to wild-type mice. ∆Hmga2 BM-derived cells took over most of hematopoiesis in competitive repopulations during serial BM transplants. When we bred mice with circulating PNH cells (Piga- mice) with ∆Hmga2 mice, the lack of GPI-linked proteins did not add an additional clonal advantage to the ∆Hmga2+ cells. In summary, our results showed that the overexpression of a 3’UTR-truncated Hmga2 leads to a proliferative hematopoiesis with clonal advantage, which may explain clonal expansion in PNH or MPN at the level of HSC. Eight independent preparations of RNA, which included each 2 samples of KLS cells and MEP cells from ∆Hmga2 mice and 2 each from WT mice. Each preparation was made from 4 or 6 mice.
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Project description:High-mobility group AT-hook 2 is a non-histone chromatin binding nuclear protein that belongs to the high-mobility group A family, which are known as "architectural transcription factors". Overexpression of HMGA2, resulting primarily due to chromosomal rearrangements of 12q15 loci, is considered a driver event in approximately 10% of uterine leiomyoma cases. To better understand how HMGA2 overexpression contributes to the formation of uterine leiomyoma, we generated primary myometrial cells engineered to overexpress HMGA2 (n=3) and determined the effect of HMGA2-overexpression on genome-wide mRNA levels, H3K27ac deposition, and chromatin accessibility.
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Project description:With the utilization of advanced tools for genome-wide studies, the role of the epigenome in regulating gene expression is becoming more evident in both normal tissue development and disease states. Uterine fibroids, also known as leiomyomas, are a major reproductive disease that manifests as benign tumors and altered extracellular matrix composition leading to severe pathological symptoms. Several genomic alterations have been associated with leiomyoma. HMGA2 overexpression has been noted in approximately 10% of all patients with leiomyoma. HMGA2 is a chromatin-targeted protein and is therefore an important contributor to altered transcriptomic outcomes. However, due to a lack of specific antibodies against HMGA2 and appropriate in vitro cellular models, there is a lack in understanding of HMGA2 interaction with and regulation of chromatin in the context of leiomyoma. To address this gap, we engineered primary myometrial cells that express V5-tagged HMGA2 at levels comparable to those observed in leiomyoma. We observed transcriptomic and H3K27 acetylation changes that appeared to drive a leiomyoma-like phenotype in the engineered HMGA2v5 cells. HMGA2 was found to be diffusedly bound to chromatin, with most of the binding occurring at promoter- distal regions. Moreover, altered chromatin accessibility was observed in HMGA2v5 cells, with enrichment of AP-1 family transcription factor binding motifs at various sites. Thus, our study suggests that overexpression of HMGA2 modulates the genomic architecture of myometrial cells to cause leiomyoma-like gene expression and epigenomic changes.
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Project description:With the utilization of advanced tools for genome-wide studies, the role of the epigenome in regulating gene expression is becoming more evident in both normal tissue development and disease states. Uterine fibroids, also known as leiomyomas, are a major reproductive disease that manifests as benign tumors and altered extracellular matrix composition leading to severe pathological symptoms. Several genomic alterations have been associated with leiomyoma. HMGA2 overexpression has been noted in approximately 10% of all patients with leiomyoma. HMGA2 is a chromatin-targeted protein and is therefore an important contributor to altered transcriptomic outcomes. However, due to a lack of specific antibodies against HMGA2 and appropriate in vitro cellular models, there is a lack in understanding of HMGA2 interaction with and regulation of chromatin in the context of leiomyoma. To address this gap, we engineered primary myometrial cells that express V5-tagged HMGA2 at levels comparable to those observed in leiomyoma. We observed transcriptomic and H3K27 acetylation changes that appeared to drive a leiomyoma-like phenotype in the engineered HMGA2v5 cells. HMGA2 was found to be diffusedly bound to chromatin, with most of the binding occurring at promoter- distal regions. Moreover, altered chromatin accessibility was observed in HMGA2v5 cells, with enrichment of AP-1 family transcription factor binding motifs at various sites. Thus, our study suggests that overexpression of HMGA2 modulates the genomic architecture of myometrial cells to cause leiomyoma-like gene expression and epigenomic changes.
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