Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Commun ; 13(1): 2267, 2022 04 27.
Article in English | MEDLINE | ID: mdl-35477713

ABSTRACT

Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.


Subject(s)
Sarcoma, Clear Cell , Soft Tissue Neoplasms , Carcinogenesis/genetics , Chromatin/genetics , Humans , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Oncogenes , RNA-Binding Protein EWS/genetics , Sarcoma, Clear Cell/genetics , Sarcoma, Clear Cell/pathology , Soft Tissue Neoplasms/genetics
2.
Life Sci Alliance ; 4(2)2021 02.
Article in English | MEDLINE | ID: mdl-33361335

ABSTRACT

Synovial sarcoma (SyS) is an aggressive mesenchymal malignancy invariably associated with the chromosomal translocation t(X:18; p11:q11), which results in the in-frame fusion of the BAF complex gene SS18 to one of three SSX genes. Fusion of SS18 to SSX generates an aberrant transcriptional regulator, which, in permissive cells, drives tumor development by initiating major chromatin remodeling events that disrupt the balance between BAF-mediated gene activation and polycomb-dependent repression. Here, we developed SyS organoids and performed genome-wide epigenomic profiling of these models and mesenchymal precursors to define SyS-specific chromatin remodeling mechanisms and dependencies. We show that SS18-SSX induces broad BAF domains at its binding sites, which oppose polycomb repressor complex (PRC) 2 activity, while facilitating recruitment of a non-canonical (nc)PRC1 variant. Along with the uncoupling of polycomb complexes, we observed H3K27me3 eviction, H2AK119ub deposition and the establishment of de novo active regulatory elements that drive SyS identity. These alterations are completely reversible upon SS18-SSX depletion and are associated with vulnerability to USP7 loss, a core member of ncPRC1.1. Using the power of primary tumor organoids, our work helps define the mechanisms of epigenetic dysregulation on which SyS cells are dependent.


Subject(s)
Chromatin Assembly and Disassembly , Chromatin/genetics , Epigenesis, Genetic , Gene Expression Regulation, Neoplastic , Sarcoma, Synovial/genetics , Binding Sites , Chromatin/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , Gene Expression Profiling , Histones/metabolism , Humans , Multiprotein Complexes/metabolism , Organoids , Protein Binding , Protein Transport , Sarcoma, Synovial/metabolism , Transcriptome
3.
Cell Rep ; 15(8): 1634-47, 2016 05 24.
Article in English | MEDLINE | ID: mdl-27184842

ABSTRACT

Cancer stem cells (CSCs) can drive tumor growth, and their maintenance may rely on post-transcriptional regulation of gene expression, including that mediated by microRNAs (miRNAs). The let-7 miRNA family has been shown to induce differentiation by silencing stem cell programs. Let-7-mediated target gene suppression is prevented by LIN28A/B, which reduce let-7 biogenesis in normal embryonic and some cancer stem cells and ensure maintenance of stemness. Here, we find that glioblastoma stem cells (GSCs) lack LIN28 and express both let-7 and their target genes, suggesting LIN28-independent protection from let-7 silencing. Using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we show that insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) binds to let-7 miRNA recognition elements (MREs) and prevents let-7 target gene silencing. Our observations define the RNA-binding repertoire of IMP2 and identify a mechanism whereby it supports GSC and neural stem cell specification.


Subject(s)
Brain Neoplasms/pathology , Gene Silencing , Glioblastoma/genetics , Glioblastoma/pathology , MicroRNAs/metabolism , Neoplastic Stem Cells/metabolism , RNA-Binding Proteins/metabolism , Base Sequence , Brain Neoplasms/genetics , Cell Adhesion , Gene Expression Regulation, Neoplastic , Humans , MicroRNAs/genetics , Neoplastic Stem Cells/pathology , Neural Stem Cells/metabolism , Protein Binding , RNA, Messenger/genetics , RNA, Messenger/metabolism , Spheroids, Cellular/pathology
SELECTION OF CITATIONS
SEARCH DETAIL
...