Age-related noncanonical TRMT6–TRMT61A signaling impairs hematopoietic stem cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA685673 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13258765.fastq.gz | Fastqsanger.gz | |||
| SRR13258766.fastq.gz | Fastqsanger.gz | |||
| SRR13258767.fastq.gz | Fastqsanger.gz | |||
| SRR13258768.fastq.gz | Fastqsanger.gz | |||
| SRR13258769.fastq.gz | Fastqsanger.gz |
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Project description:We reported the tRNA-m1A sequencing results performed in young and aged hematopoietic stem and progenitor cells. Our results defined aging-associated alterations of tRF in hematopoietic stem and progenitor cells and identifed a subset of tRF as hallmark of HSC aging.RNA-seq data analysis of WT v.s. Trmt6/61a-TG hematopoietic stem cell (lineage-, c-kit+ Sca-1+ CD135-, CD34-), the two population of hematopoietic stem cell (HSC) were purified from the bone marrow of WT and Trmt6/61a-TG mice, revealed that differnent expression of WT v.s. Trmt6/61a-TG hematopoietic stem cell.Results provide insight into the role of TRMT6/61A complex in HSC.
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Project description:In order to identify the molecular mechanism leading to the increase of TRMT6/61A complex in aged HSCs, we purified proteins interacting with TRMT6 and TRMT61A via affinity purification. HEK293T cells stably expressing SFB-tagged TRMT6 or SFB-TRMT61A were lysed in NETN buffer (20 mM Tris-HCl [pH 8.0], 100 mM NaCl, 1 mM EDTA, and 0.5% Non- idet P-40, containing protease and phosphatase inhibitors cocktail) on ice for 30 min. Cell debris were removed by centrifugation and the supernatant were collected and incubated with 50 μL S-protein beads for 4 hr at 4 ℃. Beads were washed with 1 mL NTEN buffer for three times, the immunocomplexes were boiled in 20 μL 2 x SDS loading buffer. Samples were resolved on 10% SDS-PAGE and analyzed by mass spectrometry.
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Project description:Increased protein translation plays a critical role in cancer development and treatment1,2. However, the molecular mechanism that is involved in this process remains poorly understood. N1-methyladenosine (m1A) methylation in RNA accounts for regulating mRNA translation in a post-transcriptional manner3,4. Here we show that m1A methylation levels are remarkably elevated in hepatocellular carcinoma (HCC) patient tumor tissues, especially in patients with microscopic vascular invasion (MVI). Moreover, m1A methylation signals are increased in liver cancer stem cells (CSCs) and are negatively correlated with HCC patient survival. Consistently, TRMT6 and TRMT61A, forming m1A methyltransferase complex, are highly expressed in advanced HCC tumors and are negatively correlated with HCC survival. TRMT6/TRMT61A-mediated m1A methylations are required for self-renewal of liver CSCs and tumorigenesis. Mechanistically, TRMT6/TRMT61A-dependent m1A in tRNA boost PPARδ expression, which triggers cholesterol synthesis to activate Hedgehog signaling, driving self-renewal of liver CSCs and tumorigenesis. For potential therapeutic benefit, we further identify a specific inhibitor against TRMT6/TRMT61A complex that exerts effective therapeutic effect on liver cancer with high m1A methylations. Our findings provide novel insights into the function and molecular mechanism of m1A modifications underlying liver tumorigenesis and drug target, which will serve as a new biomarker for HCC and pave a new way to develop more effective therapeutic strategies for HCC patients.
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Project description:The role of N1-methyladenosine (m1A) in cancer remains poorly understood. Here we investigate the functional importance of RNA m1A methyltransferase TRMT61A in colorectal cancer (CRC) and assess its potential as a therapeutic target. Our findings demonstrate consistent elevation of TRMT61A expression and RNA m1A levels in primary CRC tissues, which correlate significantly with poor patient survival. Through CRISPR/Cas9 screenings, TRMT61A is the most essential gene among m1A regulators. We further elucidate that TRMT61A facilitates CRC tumorigenesis and progression by enhancing the stability of mRNA of crucial targets, including ONECUT2, thereby activating the MAPK/ERK signaling pathway in an m1A-dependent manner. Of note, we show promising anti-CRC effects by inhibiting TRMT61A using nanoparticleencapsulated siTRMT61A or our identified small molecule compound, PGG. Collectively, our study uncovers the essential role of TRMT61A-m1A in CRC by activating the ONECUT2-MAPK/ERK pathway. Targeting TRMT61A holds promise as a therapeutic approach for treating CRC.
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Project description:The role of N1-methyladenosine (m1A) in cancer remains poorly understood. Here we investigate the functional importance of RNA m1A methyltransferase TRMT61A in colorectal cancer (CRC) and assess its potential as a therapeutic target. Our findings demonstrate consistent elevation of TRMT61A expression and RNA m1A levels in primary CRC tissues, which correlate significantly with poor patient survival. Through CRISPR/Cas9 screenings, TRMT61A is the most essential gene among m1A regulators. We further elucidate that TRMT61A facilitates CRC tumorigenesis and progression by enhancing the stability of mRNA of crucial targets, including ONECUT2, thereby activating the MAPK/ERK signaling pathway in an m1A-dependent manner. Of note, we show promising anti-CRC effects by inhibiting TRMT61A using nanoparticleencapsulated siTRMT61A or our identified small molecule compound, PGG. Collectively, our study uncovers the essential role of TRMT61A-m1A in CRC by activating the ONECUT2-MAPK/ERK pathway. Targeting TRMT61A holds promise as a therapeutic approach for treating CRC.
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Project description:Reprogramming of mRNA translation drives malignant transformation and cancer development. Recently, increasing studies have demonstrated that tRNA modification emerges as a critical regulator of translational reprogramming; however, its function in cancers remains largely elusive. Herein, we identify the oncogenic role of tRNA N1-methyladenosine (m1A) modification in colorectal cancer (CRC). Targeting m1A methyltransferase TRMT6 in CRC cells decreases the abundance of a specific subset of tRNAs (e.g., tRNA-Arg-ACG-1-1, tRNA-Lys-TTT-1-1) and impairs histone mRNA translation in a codon-biased manner, thus restricting histone biosynthesis and cell cycle progression. We further demonstrate that the combination of TRMT6 inhibition and CDK4/6 inhibition shows a stronger anti-cancer effect on CRC cells by synergistically inhibit histone biosynthesis. Collectively, our study reveals that tRNA m1A modification acts as a translational checkpoint of histone biosynthesis and promotes CRC progression, providing new insights for the development of efficient therapeutic strategies against CRC.
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