Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PXD006790
PROVIDER: PRJNA326952 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:FAM46C is one of the most frequently mutated genes in multiple myeloma (MM). Here, using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active non-canonical poly(A) polymerase which enhances mRNA stability and gene expression. Reintroduction of active FAM46C into MM cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induces cell death. Moreover, silencing of FAM46C in MM cells expressing WT protein enhance cell proliferation. Finally, using a FAM46C-FLAG knock-in mouse strain we show that the FAM46C protein is strongly induced during activation of primary splenocytes and that B lymphocytes isolated from newly generated FAM46C KO mice proliferate faster than those isolated from their WT littermates. Concluding, our data clearly indicate that FAM46C works as an onco-suppressor, with the specificity for B-lymphocyte lineage from which multiple myeloma originates.
2018-03-09 | PXD006790 | Pride
Project description:FAM46C is one of the most frequently mutated genes in multiple myeloma (MM) and encodes a protein of unknown function. Using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active cytoplasmic non-canonical poly(A) polymerase, which enhances mRNA stability and gene expression. Moreover, we also found that the reintroduction of active FAM46C into MM cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induced cell death. This is, to our knowledge, the first report that directly associates cytoplasmic poly(A) polymerase with carcinogenesis. Furthermore, our data suggest that the human genome encodes at least eleven non-canonical poly(A) polymerases with four FAM46 family members. Since FAM46 proteins are differentially expressed during development, these proteins may positively regulate transcript stability and translational rate in a tissue-specific manner.
2017-06-30 | GSE83772 | GEO
Project description:FAM46C, which is frequently mutated in multiple myeloma (MM), has recently been shown to encode a non-canonical poly(A) polymerase (ncPAP). However, its target mRNAs and its role in MM pathogenesis remain largely unknown. Using CRISPR-Cas9 technology and gene expression analysis we found that inactivation of FAM46C in MM downregulates immunoglobulins (Igs) and several mRNAs encoding ER-resident proteins, including some involved in unfolded protein responses (UPRs), such as PDIA6, ERP44 and EDEM2, and others that affect glycosylation, such as SSR4, AGA and DDOST. We show that FAM46C expression is induced during PC differentiation and that Ig mRNAs encoding heavy and light chains are direct substrates of the ncPAP, as revealed by poly(A) tail-length determination assays. The absence of the ncPAP results in Ig mRNA poly(A) tail-shortening, leading to a reduction in mRNA and protein abundance. On the other hand, loss of FAM46C upregulates metastasis-associated lncRNA MALAT1 and results in a sharp increase in the migration ability of MM cells. This phenotype depends mainly on the activation of PI3K/Rac1 signaling in FAM46C knockout cells since treatment with specific inhibitors substantially reduces cell mobility. This finding may have significant therapeutic implications. In conclusion, our results identify Ig mRNAs as targets of FAM46C, reveal an important function of this protein during PC maturation to increase antibody production, and show that its inactivation in MM increases cell migration and invasion, which might explain the poor prognosis of MM patients with FAM46C alterations and its role as a tumor suppressor.
2020-04-10 | GSE114984 | GEO
Project description:FAM46C is a multiple myeloma tumour suppressor whose function is only starting to be elucidated. We recently showed that in multiple myeloma cells FAM46C triggers apoptosis by inhibiting autophagy and altering intracellular trafficking and protein secretion. To date, both a physiological characterization of FAM46C role and assessment of FAM46C-induced phenotypes outside of multiple myeloma are lacking. Preliminary reports suggested an involvement of FAM46C with regulation of viral replication but results were scanty and contradictory. Here, we show that FAM46C is an IFN-stimulated gene and that expression in HEK 293T cells of wt FAM46C but not of its most frequently found mutant variants, inhibits replication of both HIV-1 and HIV-1-derived lentiviruses. We demonstrate that this effect does not require transcriptional regulation and does not depend on inhibition of either global or viral-specific translation, but rather mostly relies on FAM46C-induced deregulation of autophagy, a pathway which we show to be required for efficient lentiviral production. These studies not only provide new insights on the physiological role of the FAM46C protein but could also help implementing more efficient antiviral strategies.
2023-06-19 | PXD036818 | Pride
Project description:FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis is not determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity indicating a MM survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activates the unfolded protein response (UPR) pathway and induces mitochondrial dysfunction. In contrast, endogenous CRISPR FAM46C depletion enhanced MM cell growth and notably decreasing Ig light chain and BIP expression, activating of ERK and anti-apoptotic signaling and conferring relative resistance to dexamethasone and lenalidomide treatment. The genes altered in FAM46C depleted cells are enriched for signaling pathways regulating estrogen, glucocorticoid, B cell receptor signaling and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival. FAM46C mutation contributes to myeloma pathogenesis and disease progression by perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.
2017-07-26 | GSE99357 | GEO
Project description:FAM46C is one of the most recurrently mutated genes in multiple myeloma (MM), however its role in disease pathogenesis is not determined. Here we demonstrate that wild type (WT) FAM46C overexpression induces substantial cytotoxicity in MM cells. In contrast, FAM46C mutations found in MM patients abrogate this cytotoxicity indicating a MM survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activates the unfolded protein response (UPR) pathway and induces mitochondrial dysfunction. In contrast, endogenous CRISPR FAM46C depletion enhanced MM cell growth and notably decreasing Ig light chain and BIP expression, activating of ERK and anti-apoptotic signaling and conferring relative resistance to dexamethasone and lenalidomide treatment. The genes altered in FAM46C depleted cells are enriched for signaling pathways regulating estrogen, glucocorticoid, B cell receptor signaling and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival. FAM46C mutation contributes to myeloma pathogenesis and disease progression by perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis.
2017-07-26 | GSE99356 | GEO
Project description:Posttranscriptional regulation of mRNA is a crucial component of gene expression. The disruption of this process can have detrimental effects on normal development and give rise to various diseases. The search for novel posttranscriptional regulators and the exploration of their roles are essential for understanding development and disease. Through a multimodal analysis of red blood cell trait GWASs and transcriptomes of erythropoiesis, we identified FAM46C, a non-canonical RNA poly(A) polymerase, as a necessary factor for proper red blood cell development. FAM46C is highly expressed in late stages of the erythroid lineage, and its developmental upregulation is controlled by an erythroid-specific enhancer. We demonstrate that FAM46C stabilizes mRNA in an enzyme activity dependent manner by maintaining the poly(A) tails of its targets. Furthermore, we identified transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C, which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis. In conclusion, our study unveils a novel role of FAM46C in positively regulating the level of lysosome and mitochondria components, thereby promoting erythropoiesis.
2023-10-20 | GSE245696 | GEO
Project description:Posttranscriptional regulation of mRNA is a crucial component of gene expression. The disruption of this process can have detrimental effects on normal development and give rise to various diseases. The search for novel posttranscriptional regulators and the exploration of their roles are essential for understanding development and disease. Through a multimodal analysis of red blood cell trait GWASs and transcriptomes of erythropoiesis, we identified FAM46C, a non-canonical RNA poly(A) polymerase, as a necessary factor for proper red blood cell development. FAM46C is highly expressed in late stages of the erythroid lineage, and its developmental upregulation is controlled by an erythroid-specific enhancer. We demonstrate that FAM46C stabilizes mRNA in an enzyme activity dependent manner by maintaining the poly(A) tails of its targets. Furthermore, we identified transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C, which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis. In conclusion, our study unveils a novel role of FAM46C in positively regulating the level of lysosome and mitochondria components, thereby promoting erythropoiesis.
2023-10-20 | GSE245695 | GEO
Project description:Posttranscriptional regulation of mRNA is a crucial component of gene expression. The disruption of this process can have detrimental effects on normal development and give rise to various diseases. The search for novel posttranscriptional regulators and the exploration of their roles are essential for understanding development and disease. Through a multimodal analysis of red blood cell trait GWASs and transcriptomes of erythropoiesis, we identified FAM46C, a non-canonical RNA poly(A) polymerase, as a necessary factor for proper red blood cell development. FAM46C is highly expressed in late stages of the erythroid lineage, and its developmental upregulation is controlled by an erythroid-specific enhancer. We demonstrate that FAM46C stabilizes mRNA in an enzyme activity dependent manner by maintaining the poly(A) tails of its targets. Furthermore, we identified transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C, which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis. In conclusion, our study unveils a novel role of FAM46C in positively regulating the level of lysosome and mitochondria components, thereby promoting erythropoiesis.
2023-10-20 | GSE245694 | GEO
Project description:Posttranscriptional regulation of mRNA is a crucial component of gene expression. The disruption of this process can have detrimental effects on normal development and give rise to various diseases. The search for novel posttranscriptional regulators and the exploration of their roles are essential for understanding development and disease. Through a multimodal analysis of red blood cell trait GWASs and transcriptomes of erythropoiesis, we identified FAM46C, a non-canonical RNA poly(A) polymerase, as a necessary factor for proper red blood cell development. FAM46C is highly expressed in late stages of the erythroid lineage, and its developmental upregulation is controlled by an erythroid-specific enhancer. We demonstrate that FAM46C stabilizes mRNA in an enzyme activity dependent manner by maintaining the poly(A) tails of its targets. Furthermore, we identified transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C, which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis. In conclusion, our study unveils a novel role of FAM46C in positively regulating the level of lysosome and mitochondria components, thereby promoting erythropoiesis.
2023-10-20 | GSE245692 | GEO