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Che-1/AATF sustains cell growth and global transcription in Multiple Myeloma through the maintenance of open chromatin structure [ChIP-Seq]

ABSTRACT: Tumor transformation is the result of genetic modifications that alter gene transcription, thus producing a specific oncogenic program. However, in recent years, several exciting discoveries have shown that also aberrant epigenetic modifications play a major role in the genesis and progression of cancer. Multiple myeloma (MM) is a cancerous pathology resulting from the clonal expansion of plasma cells, and characterized by abnormal production and secretion of antibody proteins. This disease shows a great heterogeneity, caused by both genetic and epigenetic abnormalities, and despite the numerous therapeutic advances remains an incurable pathology. Here we show that the RNA Polymerase II binding protein, Che-1/AATF is required for MM cells growth by sustaining genome wide transcription and the recruitment of Pol II to the DNA. Notably, we found that Che-1 localizes on active chromatin and its depletion leads to accumulation of heterochromatin by a global decrease of histone acetylation. Moreover, we show that Che-1 directly interacts with histones and competes with HDAC class I members for histones binding. Strikingly, Che-1 downregulation decreases BRD4 chromatin accumulation and further sensitize MM cells to bromodomain and extra-terminal (BET) inhibitors. Overall, our findings identify an essential role of Che-1 in maintaining open chromatin required for sustaining MM growth, and support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100646 | GEO | 2021/06/07

REPOSITORIES: GEO

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Che-1/AATF sustains cell growth and global transcription in Multiple Myeloma through the maintenance of open chromatin structure [RNA-Seq]

Project description:Tumor transformation is the result of genetic modifications that alter gene transcription, thus producing a specific oncogenic program. However, in recent years, several exciting discoveries have shown that also aberrant epigenetic modifications play a major role in the genesis and progression of cancer. Multiple myeloma (MM) is a cancerous pathology resulting from the clonal expansion of plasma cells, and characterized by abnormal production and secretion of antibody proteins. This disease shows a great heterogeneity, caused by both genetic and epigenetic abnormalities, and despite the numerous therapeutic advances remains an incurable pathology. Here we show that the RNA Polymerase II binding protein, Che-1/AATF is required for MM cells growth by sustaining genome wide transcription and the recruitment of Pol II to the DNA. Notably, we found that Che-1 localizes on active chromatin and its depletion leads to accumulation of heterochromatin by a global decrease of histone acetylation. Moreover, we show that Che-1 directly interacts with histones and competes with HDAC class I members for histones binding. Strikingly, Che-1 downregulation decreases BRD4 chromatin accumulation and further sensitize MM cells to bromodomain and extra-terminal (BET) inhibitors. Overall, our findings identify an essential role of Che-1 in maintaining open chromatin required for sustaining MM growth, and support Che-1 as a possible target for MM therapy, alone or in combination with BET inhibitors.

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Che-1/AATF sustains cell growth and global transcription in Multiple Myeloma through the maintenance of open chromatin structure [ATAC-Seq]

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Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in Multiple Myeloma

Project description:We have strong evidence on the essential role of Che-1 protein in promoting the proliferation of MM cells by sustaining chromatin dynamics and cellular transcription on a global scale using numerous experimental approaches, including a generation of a specific transgenic mouse model.

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AATF/Che-1 localizes to paraspeckles and suppresses R-loops accumulation and interferon activation in Multiple Myeloma

Project description:We investigated the interactions of AATF/Che1 with paraspeckles complex in Multiple Myeloma(MM) cells by looking at its relationship with lncRNA NEAT1_1(NEAT1) and the essential paraspeckles proteins. By analyzing ChIP- and ChIRP-sequencing of MM cells, we assessed that the interaction between AATF/Che1 and NEAT1 occurs also onto DNA and detected the sites where they co-localize. To better characterize the interaction, we studied the effects of interfering AATF/Che1 or NEAT1 on co-localizing sites through ChIP-seq with NEAT1 interfered (GapmerNEAT1) and ChIRP-seq with AATF/Che1 interfered (siChe). We found that NEAT1 is essential in maintaining the paraspeckles complex onto those sites. Moreover, by exploring DRIP-seq data with siChe, we also detected that AATF/Che1 and NEAT1 localize on R-loops, RNA:DNA hybrid structure involved in DNA transcription and repair. A depletion of AATF/Che1 causes a further increase of those hybrid structures and the activation of the immune response in MM, in particular the interferon (IFN) activation. To further explore these findings, we performed RNA-seq with siChe and GapmerNEAT1 which confirm that AATF/Che-1 down-regulation induces a strong up-regulation of genes involved in IFN response.

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AATF interactome in human Kms27 cells

Project description:Multiple myeloma is a hematological neoplasm of plasma cells characterized by an abnormal production of immunoglobulins. Che-1/AATF (Che-1) is an RNA binding protein involved in transcription regulation and highly expressed in this malignancy. In order to better characterize its functions in this type of disease, we performed co-immunoprecipitation experiments coupled with a mass-spec analysis by using total MM Kms27 cell lysates. From this analysis we were able to identify more than 600 proteins significantly enriched in Che-1 precipitates. As expected from its role in ribosomal RNA maturation, the Che-1 interactome contains numerous proteins involved in pre-rRNA processing and several ribosomal proteins. Notably, among other proteins interacting with Che-1, we identified many essential components of the paraspeckle which play an important role in the regulation of gene expression.

2022-08-03 | PXD026659 | Pride

Che-1/miR-590-3p/TAZ axis sustains multiple myeloma disease

Project description:Multiple myeloma (MM) is a blood disease characterized by the malignant accumulation of monoclonal plasma cells in the bone marrow. Among the pathological consequences of the MM, defects in osteogenesis characterized by osteolytic lesions, osteopenia, and pathologic fractures are frequently described. Che-1/AATF (Che-1) is a co-transcriptional factor involved in MM transformation and proliferation. Here, we show that Che-1 expression in MM contributes to maintaining low level of WWTR1 (TAZ), a transcriptional coactivator downstream of the Hippo-signaling pathway. We report that the miR-590-3p, deriving from the mRNA splicing of the EIF4H host gene, can target TAZ, contributing to downregulating its expression in MM. Furthermore, we demonstrate by in vivo and in vitro experiments that Che-1 transcriptionally induces EIF4H gene. We provide data to support that miR-590-3p is secreted by MM cells in vitro and in vivo and that can inhibit TAZ levels and the physiological transcriptional expression of osteogenic-related genes, in mesenchymal stem cells. Our findings unveil an unexplored novel Che-1/miR-590-3p/TAZ axis in MM tumorigenesis by providing a rationale to explore the therapeutic potential of metastatic bone lesions.

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Expression data from Che-1 (AATF) depleted HCT 116 cell line

Project description:Che-1 is a RNA Polymerase II binding protein involved in the regulation of gene transcription. Che-1 emerges as an important adaptor that connects transcriptional regulation, cell-cycle progression, checkpoint control, and apoptosis. We have observed that Che-1 depletion sensitizes cells to chemotherapy. We used microarrays analysis to investigate classes of genes regulated by Che-1. Total RNA was extracted from control and Che-1 depleted HCT 116 cells 48 hours after transient transfection of siRNA.

2013-03-12 | E-GEOD-45009 | biostudies-arrayexpress

Expression data from Che-1 (AATF) depleted HCT 116 cell line

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AATF/Che-1 binds ribosome-associated RNAs and regulates ribosome biogenesis

Project description:AATF is a predominantly nuclear protein that has been shown to be an apoptosis-inhibiting factor essential for both embryonic development and tumor growth. Several studies have shown a role of AATF in the modulation of pivotal cellular signal transduction pathways such as p53-, mTOR- and HIF-signaling. However, the exact molecular functions underlying its essential nature to cell proliferation and survival have remained elusive. Interestingly, several lines of evidence point towards a pivotal role of this protein in ribosome biogenesis and the maturation of ribosomal RNA. The function of AATF in this process is not clear, especially since the identity of the RNA-binding protein that links the AATF-containing protein complex (ANN) to rRNA precursors is unknown. In this study, we identify AATF in a screen for RNA-binding proteins. Importantly, AATF does not only bind to polyA-tailed RNA but CLIP-experiments reveal its association with ribosomal RNA. The RNA-binding domain of AATF is essential to maintain its positive effect on cellular rRNA levels. Furthermore, AATF binds to both mRNAs encoding for ribosome biogenesis factors as well as proteins involved with this process indicating AATF to be a central hub for the coordination of ribosome maturation. Consequently, our data for the first time identify the molecular basis to the role of AATF in ribosome biosynthesis and corroborate the link between tumorigenesis and ribosome biology.

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Project description:Che-1/AATF-induced transcriptionally active chromatin promotes cell proliferation in Multiple Myeloma

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