B cell humoral response and differentiation is regulated by non-canonical poly(A) polymerase TENT5C.
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ABSTRACT:
PROVIDER: PRJNA549395 | ENA |
REPOSITORIES: ENA
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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: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 | GSE245692 | 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 | GSE245693 | GEO
Project description:TENT5C is a non-canonical cytoplasmic poly(A) polymerase highly expressed by activated B cells to suppress their proliferation. Here we measure the global distribution of poly(A) tail lengths in responsive B cells using a Nanopore direct RNA-sequencing approach, showing that TENT5C polyadenylates immunoglobulin mRNAs regulating their half-life and consequently steady-state levels. TENT5C is upregulated in differentiating plasma cells by innate signaling. Compared with wild-type, Tent5c-/- mice produce fewer antibodies and have diminished T-cell-independent immune response despite having more CD138high plasma cells as a consequence of accelerated differentiation. B cells from Tent5c-/- mice also have impaired capacity of the secretory pathway, with reduced ER volume and unfolded protein response. Importantly, these functions of TENT5C are dependent on its enzymatic activity as catalytic mutation knock-in mice display the same defect as Tent5c-/-. These findings define the role of the TENT5C enzyme in the humoral immune response.
| S-EPMC7184606 | biostudies-literature
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:TENT4A (PAPD7) is a non-canonical poly(A) polymerase, of which little is known. Here we show that TENT4A is involved in the regulation of multiple biological pathways, and focus on translesion DNA synthesis (TLS), a DNA-damage tolerance process in which unrepaired lesions are bypassed by error-prone DNA polymerases. We show that TENT4A regulates mRNA stability and/or translation of DNA polymerase η, and of the RAD18 E3 ligase that monoubiquitinates PCNA, the latter being a key step in TLS which enables recruitment of error-prone DNA polymerases to damaged DNA sites. Remarkably, in addition to the effect on RAD18 mRNA stability via controlling its poly(A) tail, TENT4A indirectly regulates RAD18 via the tumor suppressor CYLD, and via the long non-coding antisense RNA PAXIP1-AS2, which had no known function. Knocking down the expression of TENT4A or CYLD, or over-expression of PAXIP1-AS2 led each to a decrease in the amount of the RAD18 protein, but the effect on PCNA ubiquitination was variable. Still, TLS was reduced under these conditions, likely due a to a parallel decrease in DNA polymerase η. Bioinformatics analysis revealed that TLS error-prone DNA polymerase genes and their TENT4A-related regulators are frequently mutated in endometrial cancer genomes, suggesting that TLS is dysregulated in endometrial cancer.
2021-06-29 | GSE141870 | GEO
Project description:B cell humoral response and differentiation is regulated by non-canonical poly(A) polymerase TENT5C.
| PRJEB33089 | ENA