ALKBH1-mediated tRNA 5-formylcytidine modification facilitates codon-biased translation and leukemogenesis [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1083976 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:ALKBH1-mediated tRNA 5-formylcytidine modification facilitates codon-biased translation and leukemogenesis [Ribosome-seq]
| PRJNA1083975 | ENA
Project description:Here, we show that ALKBH1 is overexpressed in acute myeloid leukemia (AML) and required for AML development/maintenance and leukemia stem cell (LSC) self-renewal, but is dispensable for normal hematopoiesis. ALKBH1 plays a pivotal role in regulating mitochondrion structure/functions and facilitating oxidative phosphorylation (OXPHOS) to generate energy for AML cell survival/proliferation. Mechanistically, we uncover that ALKBH1 specifically promotes 5-formylcytidine (f5C) formation in tRNAs to expand tRNA decoding capacity and promote translation of essential targets. This mechanism/phenomenon is termed “epitranscriptomic Midas touch”, which promotes expression of WDR43 and BCL2, two crucial targets of ALKBH1 in AML. ALKBH1 targeting markedly enhances BCL2 inhibitor (Venetoclax)’s efficacy in AML treatment. Collectively, our studies reveal the functional importance of a previously unappreciated signaling (i.e., ALKBH1/tRNA-f5C/WDR43/BCL2) in AML, and highlight the potential of targeting ALKBH1 for cancer therapy.
2025-07-23 | GSE260906 | GEO
Project description:Here, we show that ALKBH1 is overexpressed in acute myeloid leukemia (AML) and required for AML development/maintenance and leukemia stem cell (LSC) self-renewal, but is dispensable for normal hematopoiesis. ALKBH1 plays a pivotal role in regulating mitochondrion structure/functions and facilitating oxidative phosphorylation (OXPHOS) to generate energy for AML cell survival/proliferation. Mechanistically, we uncover that ALKBH1 specifically promotes 5-formylcytidine (f5C) formation in tRNAs to expand tRNA decoding capacity and promote translation of essential targets. This mechanism/phenomenon is termed “epitranscriptomic Midas touch”, which promotes expression of WDR43 and BCL2, two crucial targets of ALKBH1 in AML. ALKBH1 targeting markedly enhances BCL2 inhibitor (Venetoclax)’s efficacy in AML treatment. Collectively, our studies reveal the functional importance of a previously unappreciated signaling (i.e., ALKBH1/tRNA-f5C/WDR43/BCL2) in AML, and highlight the potential of targeting ALKBH1 for cancer therapy.
2025-07-23 | GSE260905 | GEO
Project description:The dynamic balance between tRNA supply and codon usage demand is a fundamental principle in the cellular translation economy. However, the regulation and functional consequences of this balance remain unclear. Here, we use PARIS2 interactome capture, structure modeling, conservation analysis, RNA–protein interaction analysis, and modification mapping to reveal the targets of hundreds of snoRNAs, many of which were previously considered orphans. We identify a snoRNA–tRNA interaction network that is required for global tRNA modifications, including 2′-O-methylation and others. Loss of Fibrillarin, the snoRNA-guided 2′-O-methyltransferase, induces global upregulation of tRNA fragments, a large group of regulatory RNAs. In particular, the snoRNAs D97/D133 guide the 2′-O-methylation of multiple tRNAs, especially for the amino acid methionine (Met), a protein-intrinsic antioxidant. Loss of D97/D133 snoRNAs in human HEK293 cells reduced target tRNA levels and induced codon adaptation of the transcriptome and translatome. Both D97/D133 single and double knockouts in HEK293 cells suppress Met-enriched proliferation-related gene expression programs, including, translation, splicing, and mitochondrial energy metabolism, and promote Met-depleted programs related to development, differentiation, and morphogenesis. In a mouse embryonic stem cell model of development, knockdown and knockout of D97/D133 promote differentiation to mesoderm and endoderm fates, such as cardiomyocytes, without compromising pluripotency, consistent with the enhanced development-related gene expression programs in human cells. This work solves a decade-old mystery about orphan snoRNAs and reveals a function of snoRNAs in controlling the codon-biased dichotomous cellular states of proliferation and development.
2023-09-21 | GSE234689 | GEO
Project description:A snoRNA–tRNA modification network governs codon-biased cellular states
| PRJNA982754 | ENA
Project description:The dynamic balance between tRNA supply and codon usage demand is a fundamental principle in the cellular translation economy. However, the regulation and functional consequences of this balance remain unclear. Here, we use PARIS2 interactome capture, structure modeling, conservation analysis, RNA–protein interaction analysis, and modification mapping to reveal the targets of hundreds of snoRNAs, many of which were previously considered orphans. We identify a snoRNA–tRNA interaction network that is required for global tRNA modifications, including 2′-O-methylation and others. Loss of Fibrillarin, the snoRNA-guided 2′-O-methyltransferase, induces global upregulation of tRNA fragments, a large group of regulatory RNAs. In particular, the snoRNAs D97/D133 guide the 2′-O-methylation of multiple tRNAs, especially for the amino acid methionine (Met), a protein-intrinsic antioxidant. Loss of D97/D133 snoRNAs in human HEK293 cells reduced target tRNA levels and induced codon adaptation of the transcriptome and translatome. Both D97/D133 single and double knockouts in HEK293 cells suppress Met-enriched proliferation-related gene expression programs, including, translation, splicing, and mitochondrial energy metabolism, and promote Met-depleted programs related to development, differentiation, and morphogenesis. In a mouse embryonic stem cell model of development, knockdown and knockout of D97/D133 promote differentiation to mesoderm and endoderm fates, such as cardiomyocytes, without compromising pluripotency, consistent with the enhanced development-related gene expression programs in human cells. This work solves a decade-old mystery about orphan snoRNAs and reveals a function of snoRNAs in controlling the codon-biased dichotomous cellular states of proliferation and development.
2023-09-21 | GSE234599 | GEO
Project description:The dynamic balance between tRNA supply and codon usage demand is a fundamental principle in the cellular translation economy. However, the regulation and functional consequences of this balance remain unclear. Here, we use PARIS2 interactome capture, structure modeling, conservation analysis, RNA–protein interaction analysis, and modification mapping to reveal the targets of hundreds of snoRNAs, many of which were previously considered orphans. We identify a snoRNA–tRNA interaction network that is required for global tRNA modifications, including 2′-O-methylation and others. Loss of Fibrillarin, the snoRNA-guided 2′-O-methyltransferase, induces global upregulation of tRNA fragments, a large group of regulatory RNAs. In particular, the snoRNAs D97/D133 guide the 2′-O-methylation of multiple tRNAs, especially for the amino acid methionine (Met), a protein-intrinsic antioxidant. Loss of D97/D133 snoRNAs in human HEK293 cells reduced target tRNA levels and induced codon adaptation of the transcriptome and translatome. Both D97/D133 single and double knockouts in HEK293 cells suppress Met-enriched proliferation-related gene expression programs, including, translation, splicing, and mitochondrial energy metabolism, and promote Met-depleted programs related to development, differentiation, and morphogenesis. In a mouse embryonic stem cell model of development, knockdown and knockout of D97/D133 promote differentiation to mesoderm and endoderm fates, such as cardiomyocytes, without compromising pluripotency, consistent with the enhanced development-related gene expression programs in human cells. This work solves a decade-old mystery about orphan snoRNAs and reveals a function of snoRNAs in controlling the codon-biased dichotomous cellular states of proliferation and development.
2023-09-21 | GSE234687 | GEO
Project description:The dynamic balance between tRNA supply and codon usage demand is a fundamental principle in the cellular translation economy. However, the regulation and functional consequences of this balance remain unclear. Here, we use PARIS2 interactome capture, structure modeling, conservation analysis, RNA–protein interaction analysis, and modification mapping to reveal the targets of hundreds of snoRNAs, many of which were previously considered orphans. We identify a snoRNA–tRNA interaction network that is required for global tRNA modifications, including 2′-O-methylation and others. Loss of Fibrillarin, the snoRNA-guided 2′-O-methyltransferase, induces global upregulation of tRNA fragments, a large group of regulatory RNAs. In particular, the snoRNAs D97/D133 guide the 2′-O-methylation of multiple tRNAs, especially for the amino acid methionine (Met), a protein-intrinsic antioxidant. Loss of D97/D133 snoRNAs in human HEK293 cells reduced target tRNA levels and induced codon adaptation of the transcriptome and translatome. Both D97/D133 single and double knockouts in HEK293 cells suppress Met-enriched proliferation-related gene expression programs, including, translation, splicing, and mitochondrial energy metabolism, and promote Met-depleted programs related to development, differentiation, and morphogenesis. In a mouse embryonic stem cell model of development, knockdown and knockout of D97/D133 promote differentiation to mesoderm and endoderm fates, such as cardiomyocytes, without compromising pluripotency, consistent with the enhanced development-related gene expression programs in human cells. This work solves a decade-old mystery about orphan snoRNAs and reveals a function of snoRNAs in controlling the codon-biased dichotomous cellular states of proliferation and development.
2023-09-21 | GSE234598 | GEO
Project description:A snoRNA–tRNA modification network governs codon-biased cellular states [RMseq]
| PRJNA982109 | ENA
Project description:Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming (tRNA-Seq)
| PRJNA1026841 | ENA