Gene expression profiling of low-grade fibromyxoid sarcoma (LGFMS)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE24369 | GEO | 2011/05/02
SECONDARY ACCESSION(S): PRJNA132963
REPOSITORIES: GEO
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Project description:Analysis of gene expression in 17 low-grade fibromyxoid sarcoma (LGFMS) samples compared to that of histologically similar tumors. LGFMS is characterized by the specific translocations t(7;16)(q33;p11) or t(11;16)(p11;p11) and corresponding fusion genes FUS-CREB3L2 or FUS-CREB3L1. The results identifies a LGFMS-specific gene expression profile and provide insight into FUS-CREB3L2 regulated gene expression. RNA was extracted from 17 LGFMS tumor biopsies and hybridized to Affymetrix arrays. RNA from 6 myxofibrosarcoma (MFS), 6 desmoid fibromatosis (DFM), 5 solitary fibrous tumor (SFT) and 6 extraskeletal myxoid chondrosarcoma (EMCS) tumor biopsies was used as comparison. Two pools of skeletal muscle RNA was also included in the comparison.
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Project description:For this study, we selected, from the French Sarcoma Group (FSG) database, soft tissue sarcomas with no recurrent chromosomal translocations and for which a frozen tissue of the untreated primary tumor was available. Three hundred and ten sarcomas have been studied. They are split in two cohorts. We used microarrays to detail the global programme of gene expression underlying the tumor biology Every cases has been histologically reviewed by the pathologist subgroup and classified according to the 2002 WHO classification using histology, immunohistochemistry and molecular genetic and cytogenetic when needed
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Project description:Abstract: Secretion occurs in all cells, with relatively low levels in most cells and extremely high levels in specialized secretory cells, such as those of the pancreas, salivary and mammary glands. Here, we report that the CrebA/Creb3-like family of bZip transcription factors functions to upregulate expression of both the general protein machinery required in all cells for secretion and of cell-type specific secreted proteins. Drosophila CrebA directly binds the enhancers of secretory pathway genes and is both necessary and sufficient to activate expression of every secretory pathway component gene examined thus far. Microarray profiling reveals that CrebA also upregulates expression of genes encoding cell type specific secreted components. Finally, we find that the human CrebA orthologues, Creb3L1 and Creb3L2, have the ability to upregulate the secretory pathway in non-secretory cell types. Goals: Creb3L1 is the closest related human orthologue of Drosophila CrebA. CrebA is required to upregulate genes encoding the protein machinery and cargo in specialized secretory cells. To determine if the human orthologues of CrebA, Creb3L1 and Creb3L2, perform the same function, we expressed the truncated active form of Creb3L1 in non-secretory HeLa cells. We then performed microarray experiments and found that active Creb3L1 is sufficient to upregulate genes encoding the protein machinery of the secretory pathway, as observed with Drosophila CrebA. HeLa cells were transiently co-transfected with truncated Creb3L1 (Creb3L1 T) and GFP. Following 20 hours in culture, GFP positive cells were isolated by FACS and RNA was extracted using the Rneasy kit (Qiagen). As a control, mock transfected cells were also subjected to cell sorting and RNA was extracted using the same protocols. At least three replicates were obtained for each group.
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Project description:The FET family of fusion oncogenes carry one of the three genes, FUS, EWSR1 or TAF15, as 5’‑partners juxtaposed to one of many different DNA binding transcription factor genes as 3’‑partners. FET fusion oncogenes are pathognomonic for many types of sarcoma and leukemia, such as FUS-DDIT3 in myxoid liposarcoma (MLS) and EWSR1-FLI1 in Ewing sarcoma (EWS). We used recombinant FET N-terminal domains in a pulldown screen to find interaction partners to the FET proteins and identified components of the SWI/SNF complex. The ~2 MDa SWI/SNF chromatin remodeling complex utilizes energy from ATP hydrolysis to remodel nucleosomes and expose DNA. We used immunoprecipitation followed by mass spectrometry or western blot analysis to extensively characterize the interaction between FET fusion oncoproteins and the SWI/SNF complex.
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Project description:Fused in sarcoma (FUS) encodes a low complexity RNA-binding protein with diverse roles in transcriptional activation and RNA processing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). FUS has also been implicated in DNA double-strand break repair (DSBR) and genome maintenance. However, the underlying mechanisms are unknown. Here we employed quantitative proteomics, transcriptomics, and DNA copy number analysis (Sort-Seq), in conjunction with FUS-/- cells to ascertain roles of FUS in genome protection. FUS-/- cells exhibited alterations in the recruitment and retention of DSBR factors BRCA1 and 53BP1 but were not overtly sensitive to genotoxins. By contrast, FUS-deficient cells had reduced proliferative potential that correlated with reduced replication fork speed, diminished loading of pre-replication complexes, and attenuated expression of S-phase associated genes. FUS interacted with lagging strand DNA synthesis factors and other replisome components, but did not translocate with active replication forks. Using a Sort-Seq workflow, we show that FUS contributes to genome-wide control of DNA replication timing and is essential for the early replication of transcriptionally active DNA. These findings illuminate new roles for FUS in DNA replication initiation and timing that may contribute to genome instability and functional defects in cells harboring disease-associated FUS fusions.
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Project description:Ewing sarcoma (EwS) is an adolescent and young adult sarcoma characterized by chromosome translocations between members of the FET family of RNA binding proteins and members of the ETS family of transcription factors, the most frequent fusion being EWS-FLI1. EWS-FLI1 acts as a pioneer factor, creating de novo enhancers and activating genes located in the vicinity of EWS-FLI1-bound microsatellite sequences. recent results from our lab indicate that EWS-FLI1, which activates transcription through binding to the DNA at specific sites, can generate fully novel, unconventional transcription units in regions of the genome that are fully quiescent in normal cells (manuscript in preparation). The hypothesis of the project is that the open reading frames (ORFs) of these transcripts may encode peptides presented at the cell surface by HLA class I molecules and hence be recognized as non-self by the immune system. The aim of this study is to detect Ewing-specific neo-peptides/proteins using proteomics approach.
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