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TUT1-catalyzed U6 snRNA 3′-end maturation is required for mRNA splicing to maintain stem cell pools during embryogenesis [Nanopore long-read RNA-seq]

ABSTRACT: The post-transcriptional maturation of U6 snRNA 3′-end is important for spliceosomal assembly and RNA splicing, and is catalyzed by sequential enzymatic activities of TUT1 and USB1, that is, an oligo(U) tail is first added by TUT1 to the freshly transcribed U6 snRNA, and then trimmed by USB1 to generate mature U6 snRNA. However, biallelic inactivation of TUT1 or USB1 is linked to distinct human developmental disorders, and their physiological functions remain unknown. Here, using multiple genetically engineered mouse models, we show that Tut1, but unexpectedly not Usb1, is essential for the maintenance of the epiblast and neural stem cells in vivo. Loss of Tut1 weakens the interactions between essential splicing factors and U6 snRNA, causes defective RNA splicing, and triggers massive DNA damage and subsequent cell death. Importantly, cell death can be prevented by recombinant U6 snRNA containing an oligo(U) tail. These results challenge the current model of U6 snRNA 3′-end maturation and function. We propose that TUT1 is an essential U6 snRNA 3′-end maturation or repair factor, and discuss the implications of these results for understanding the etiologies of TUT1- and USB1-related human disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE305664 | GEO | 2026/06/03

REPOSITORIES: GEO

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TUT1-catalyzed U6 snRNA 3′-end maturation is required for mRNA splicing to maintain stem cell pools during embryogenesis [RNA-Seq]

Project description:The post-transcriptional maturation of U6 snRNA 3′-end is important for spliceosomal assembly and RNA splicing, and is catalyzed by sequential enzymatic activities of TUT1 and USB1, that is, an oligo(U) tail is first added by TUT1 to the freshly transcribed U6 snRNA, and then trimmed by USB1 to generate mature U6 snRNA. However, biallelic inactivation of TUT1 or USB1 is linked to distinct human developmental disorders, and their physiological functions remain unknown. Here, using multiple genetically engineered mouse models, we show that Tut1, but unexpectedly not Usb1, is essential for the maintenance of the epiblast and neural stem cells in vivo. Loss of Tut1 weakens the interactions between essential splicing factors and U6 snRNA, causes defective RNA splicing, and triggers massive DNA damage and subsequent cell death. Importantly, cell death can be prevented by recombinant U6 snRNA containing an oligo(U) tail. These results challenge the current model of U6 snRNA 3′-end maturation and function. We propose that TUT1 is an essential U6 snRNA 3′-end maturation or repair factor, and discuss the implications of these results for understanding the etiologies of TUT1- and USB1-related human disorders.

2026-06-03 | GSE305663 | GEO

TUT1 and USB1, the biogenesis enzymes for 2′,3′-cyclic phosphate modification at U6 snRNA 3’ end, have distinct roles in mammalian development [scRNA-seq]

Project description:The 3’ end of most cellular U6 snRNA has a 2′,3′-cyclic phosphate group, a post-transcriptional modification thought to be essential for proper RNA splicing and cellular function. Recent studies have established that the biogenesis of 2′,3′-cyclic phosphate requires two enzymes: first TUT1 adds a poly(U) tail to the 3’ end of U6 snRNA, followed by USB1-catalyzed trimming of the poly(U) tail. Here, we use nine genetically engineered mouse models of Tut1 and Usb1 to show that, contrary to what was previously believed, Usb1 and thus 2′,3′-cyclic phosphate is dispensable for intra-embryonic cell lineages. We find that Tut1, but not Usb1, is essential for the maintenance of the epiblast and neural stem cells. Loss of Tut1 causes defective RNA splicing, triggering massive DNA damage and subsequent cell death. In contrast, loss of Usb1 primarily damages endothelial cells of the extra-embryonic vasculature in the yolk sac by both cell-intrinsic and -extrinsic mechanisms, leading to fetal growth restriction. These results demonstrate that TUT1-catalyzed U6 snRNA 3’ end oligouridylation, rather than 2′,3′-cyclic phosphate as previously thought, is required for proper RNA splicing. Further studies are warranted to elucidate how these different post-transcriptional modifications regulate the function of U6 snRNA in RNA splicing in development and disease.

2026-06-03 | GSE277839 | GEO

TUT1 and USB1, the biogenesis enzymes for 2′,3′-cyclic phosphate modification at U6 snRNA 3’ end, have distinct roles in mammalian development [Nanopore]

2026-06-03 | GSE277838 | GEO

TUT1 and USB1, the biogenesis enzymes for 2′,3′-cyclic phosphate modification at U6 snRNA 3’ end, have distinct roles in mammalian development [RNA-seq]

2026-06-03 | GSE277835 | GEO

TUT1 promotes PDAC progression through Alternative Splicing [3‘-seq]

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a malignant cancer with high lethality rate. In this study, we identify that terminal Uridylyl Transferase 1 (TUT1), a specific terminal uridylyltransferase for U6 snRNA, is required for survival of PDAC, but not for that of normal adult pancreas. Mechanistically, TUT1 uridylylation activity promotes tri-snRNP assembly though facilitating the binding of LSM protein to U6 snRNA. TUT1 deletion leads to global alternative splicing (AS) changes which in turn triggers PDAC cell cycle dysregulation. Here, we reveal a novel function of TUT1 in regulating AS by modulating tri-snRNP levels and identify TUT1 as a potential therapeutic target for the treatment of PDAC.

2025-01-11 | GSE212513 | GEO

TUT1 promotes PDAC progression through Alternative Splicing [RNA-seq]

2025-01-11 | GSE212514 | GEO

QKI ensures splicing fidelity during cardiogenesis by engaging the U6 tri-snRNP to activate splicing at weak 5’splice sites [eCLIP HEK293xT]

Project description:During organogenesis, the establishment of tissue architecture requires precise RNA processing. Many developmentally essential exons bear weak 5′ splice sites (5′SS) yet are spliced with high precision, implying unknown yet active splicing fidelity mechanisms. Combining transcriptome and alternative splicing profiling and with temporal eCLIP mapping of RNA interactions across development, we identify the RNA-binding protein QKI as an essential direct regulator of splicing fidelity in key cardiac transcripts. Although QKI is dispensable for cardiac lineage specification, its loss disrupts sarcomere assembly despite intact expression of sarcomere mRNAs through exon skipping and intron retention in key sarcomeric mRNAs. QKI-dependent exons in essential cardiac genes have weak 5′SS and frequently show poor complementarity with U6 snRNA; we show that QKI directly interacts with U6 snRNA using an overlapping interface to its traditional intronic binding activity, securing U4/U6·U5 tri-snRNP recruitment to ensure exon inclusion. Thus, QKI exemplifies how context-aware RBPs enforce splicing fidelity at structurally vulnerable splice sites by coupling local intronic cues to spliceosome engagement, thereby securing accurate exon inclusion during organogenesis.

2025-09-17 | GSE306688 | GEO

QKI ensures splicing fidelity during cardiogenesis by engaging the U6 tri-snRNP to activate splicing at weak 5’splice sites [RNA-Seq]

2025-09-17 | GSE306690 | GEO

QKI ensures splicing fidelity during cardiogenesis by engaging the U6 tri-snRNP to activate splicing at weak 5’splice sites [eCLIP Hues6]

2025-09-17 | GSE306579 | GEO

yeast U6 3' RACE

Project description:Mpn1 proteins are evolutionarily conserved exonucleases that modify spliceosomal U6 small nuclear RNAs (snRNAs) post-transcriptionally. Mutations in the human MPN1 gene are associated to the genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Mpn1 deficiency leads to aberrant U6 3M-bM-^@M-^Y end processing and accelerated U6 decay through unknown molecular mechanisms. Here we show that in mpn1M-NM-^T fission yeast cells U6 is barely bound by the protective Lsm2-8 complex, undergoes extensive oligoadenylation and is degraded by the nuclear RNA exonuclease Rrp6 independently of the poly(A) polymerase Cid14/Trf4. Mpn1 processes U6 in a spliceosome-dependent manner, as mutant U6 molecules that fail to join the spliceosome are not substrates for Mpn1. Moreover, human U6atac, the U6-like snRNA of the minor spliceosome, is a novel substrate for hMpn1. We unveil mechanistic details of a new U6 degradation pathway and further corroborate the notion that inefficient canonical and minor pre-mRNA splicing promotes PN. the 3' termini of U6 or tagged-U6 species from the indicated mutant cells were compared to wt yeast strain

2014-08-08 | E-GEOD-60195 | biostudies-arrayexpress

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