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Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [N40K mice RNA-seq]

ABSTRACT: Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, neuronal degeneration, cognitive impairment, and erroneous splicing events in synaptic pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE196871 | GEO | 2022/08/11

REPOSITORIES: GEO

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Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment [N40K neuron RNA-seq]

Project description:Recent proteome and transcriptome profiling of Alzheimer's disease (AD) brains reveals RNA splicing dysfunction and U1 small nuclear ribonucleoprotein (snRNP) pathology containing U1-70K and its N-terminal 40-KDa fragment (N40K). Here we present a causative role of U1 snRNP dysfunction to neurodegeneration in primary neurons and transgenic mice (N40K-Tg), in which N40K expression exerts a dominant-negative effect to downregulate full-length U1-70K. N40K-Tg recapitulates N40K insolubility, neuronal degeneration, cognitive impairment, and erroneous splicing events in synaptic pathways.

2022-08-11 | GSE196872 | GEO

iCLIP and NGS to map protein-RNA interactions for U1-snRNP proteins in Trypanosoma brucei

Project description:Individual-nucleotide resolution UV-crosslinking and immunoprecipitation (iCLIP) combined with high-throughput sequencing was performed to generate genome-wide binding maps of two U1-snRNP proteins: U1C and U1-70K in Trypanosoma brucei. 3 (2) biological replicates of U1C (U1-70K) -specific co-immunoprecipitated RNA after UV-crosslinking

2014-05-16 | E-GEOD-43848 | biostudies-arrayexpress

Neuronal expression of Alzheimer's disease-associated U1-70K cleavage product causes splicing dysfunction and cognitive impairment in mice

Project description:Alzheimer's disease (AD) displays progressive cognitive decline that is associated with protein ß-amyloid and tau aggregation, but the causative mechanisms are not fully understood. Recent proteomics profiling has identified, in sporadic and familial cases, a tangle-like pathology of U1 small nuclear ribonucleoprotein complex (snRNP), containing U1-70K and its N-terminal cleavage product (N40K), with RNA splicing alteration. To determine whether U1 snRNP dysfunction may play a causative role in AD, we generate a transgenic mouse model (N40K-Tg) by neuronal expression of N40K. Deep transcriptomic analysis of N40K-Tg mice was performed to evaluate intron-retaining mRNAs. Tissue was extracted from hippocampus at three month and twelve month comparing N40K-Tg vs WT mice.

2022-08-11 | GSE115177 | GEO

iCLIP and NGS to map protein-RNA interactions for U1-snRNP proteins in Trypanosoma brucei

2014-05-16 | GSE43848 | GEO

Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment

Project description:Alzheimer’s disease-associated U1 snRNP splicing dysfunction causes neuronal hyperexcitability and cognitive impairment

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Selected humanization of yeast U1 snRNP leads to global suppression of pre-mRNA splicing and mitochondrial dysfunction in the budding yeast

Project description:The recognition of 5’ splice site (5’ ss) is one of the earliest steps of pre-mRNA splicing. To better understand the mechanism and regulation of 5’ ss recognition, we selectively humanized components of the yeast U1 snRNP to reveal the function of these components in 5’ ss recognition and splicing. We targeted U1C and Luc7, two proteins that interact with and stabilize the yeast U1 (yU1) snRNA and the 5’ ss RNA duplex. We replaced the Zinc-Finger (ZnF) domain of yU1C with its human counterpart, which resulted in cold-sensitive growth phenotype and moderate splicing defects. Next, we added an auxin-inducible degron to yLuc7 protein and found that Luc7-depleted yU1 snRNP resulted in the concomitant loss of PRP40 and Snu71 (two other essential yeast U1 snRNP proteins), and further biochemical analyses suggest a model of how these three proteins interact with each other in the U1 snRNP. The loss of these proteins resulted in a significant growth retardation accompanied by a global suppression of pre-mRNA splicing. The splicing suppression led to mitochondrial dysfunction as revealed by a release of Fe2+ into the growth medium and an induction of mitochondrial reactive oxygen species. Together, these observations indicate that the human U1C ZnF can substitute that of yeast, Luc7 is essential for the incorporation of the Luc7-Prp40-Snu71 trimer into yeast U1 snRNP, and splicing plays a major role in the regulation of mitochondria function in yeast.

2024-01-03 | GSE252348 | GEO

Promoter directionality is controlled by U1 snRNP and polyadenylation signals

Project description:Transcription of the mammalian genome is pervasive, but productive transcription outside of protein-coding genes is limited by unknown mechanisms. In particular, although RNA polymerase II (RNAPII) initiates divergently from most active gene promoters, productive elongation occurs primarily in the sense-coding direction. Here we show in mouse embryonic stem cells that asymmetric sequence determinants flanking gene transcription start sites control promoter directionality by regulating promoter-proximal cleavage and polyadenylation. We find that upstream antisense RNAs are cleaved and polyadenylated at poly(A) sites (PASs) shortly after initiation. De novo motif analysis shows PAS signals and U1 small nuclear ribonucleoprotein (snRNP) recognition sites to be the most depleted and enriched sequences, respectively, in the sense direction relative to the upstream antisense direction. These U1 snRNP sites and PAS sites are progressively gained and lost, respectively, at the 5' end of coding genes during vertebrate evolution. Functional disruption of U1 snRNP activity results in a dramatic increase in promoter-proximal cleavage events in the sense direction with slight increases in the antisense direction. These data suggest that a U1-PAS axis characterized by low U1 snRNP recognition and a high density of PASs in the upstream antisense region reinforces promoter directionality by promoting early termination in upstream antisense regions, whereas proximal sense PAS signals are suppressed by U1 snRNP. We propose that the U1-PAS axis limits pervasive transcription throughout the genome. 3' end sequencing of poly (A) + RNAs in mouse ES cells with and without U1 snRNP inhibition using antisense morpholino oligonucleotides (AMO). Each with two biological replicates.

2013-06-28 | E-GEOD-46433 | biostudies-arrayexpress

Frac-Seq Analysis of ZFC3H1 Knockdown U2OS Cells

Project description:We have found that depletion of the zinc finger protein ZFC3H1 inhibits the nuclear retention of these RNAs. ZFC3H1 forms a complex with MTR4 and PABPN1 (the PolyAdenylation EXosome Targeting complex (Meola et al 2016, Ogami et al 2017) and likely recruits the nuclear exosome for RNA degradation. Recently, we found that depletion of U1-70K, one protein component of the U1 snRNP spliceosomal complex, inhibits nuclear retention of 5’SS motif containing RNAs. The U1 snRNP complex recognizes and binds to the 5’SS motif and in vitro studies showed that U1-70K directly interact with a similar 5’SS motif through U1 snRNA binding (Gunderson et al 1999). Interestingly, we found that U1 snRNP is involved in targeting 5’SS motif containing mRNAs to nuclear speckles shortly following RNA transcription. In contrast, ZFC3H1 is involved in nuclear speckle localization post-transcriptionally and actively retain RNAs in these structures. Together, our results suggest a model where U1 snRNP interacts with the RNA via the 5’SS motif and targets mature mRNAs to nuclear speckles. Specifically, it suggests that misprocessed RNAs can be targeted to speckles (or other nucleoplasmic foci) and that these foci serve as a platform to recruit the nuclear exosome via ZFC3H1. Our results highlight a splicing independent role of U1 snRNP and how mRNA nuclear export function in nuclear surveillance to prevent the translation of aberrant proteins.

2022-03-31 | GSE176144 | GEO

ALS-causative mutations in FUS/TLS confer gain- and loss-of-function by altered association with SMN and U1-snRNP

Project description:The RNA-binding protein FUS/TLS, mutation in which is causative of the fatal motor neuron disease ALS, is demonstrated to directly bind to the U1-snRNP and SMN complexes. ALS-causative mutations in FUS/TLS are shown to abnormally enhance their interaction with SMN and reduce interaction with U1-snRNP. Correspondingly, global RNA analysis reveals a mutant-dependent loss of splicing activity, with ALS-linked mutants failing to reverse changes caused by loss of wild-type FUS/TLS. Furthermore, a common FUS/TLS mutant-associated RNA splicing signature is identified in ALS patient fibroblasts. Taken together, our studies establish potentially converging disease mechanisms in ALS and spinal muscular atrophy, with ALS-causative mutants acquiring properties representing both gain (dysregulation of SMN) and loss (reduced RNA processing mediated by U1-snRNP) of function. RNA-mediated oligonucleotide Annealing, Selection, and Ligation with Next-Generation sequencing (RASL-seq) method was used for analyzing alternative splicing changes. Oligonucleotide probes are designed to anneal to the exon-exon junctions. The probe library was assembled to assess 5530 unique alternative splicing events, most of which were exon inclusion or skipping, with a minority for alternative 5’- or 3’- splice sites. The splicing changes were compared among groups of reducing FUS/TLS or SMN levels, or expressing various FUS mutations to determine the loss versus gain of FUS/TLS function on splicing regulation.

2015-02-10 | E-GEOD-64078 | biostudies-arrayexpress

Neuronal stimulation changes U1 snRNP binding and intronic polyadenylation

Project description:Synaptic activity induces well-known changes in enhancer-promoter driven gene expression but also induces changes in splicing and polyadenylation that are understudied. Here, we investigate the mechanism of expression for alternative polyadenylation isoform Homer1a, an immediate early gene essential to synaptic plasticity. We report that neuronal activation, in neuronal cultures and in adult mouse brain, depletes the splice factor U1 snRNP from Homer1 pre-mRNA and that this causes shifted utilization of a cryptic polyadenylation signal within intron 5 resulting in Homer1a expression. Because U1 snRNP is a ubiquitous splice factor, we tested the generality of activity-driven U1 snRNP depletion as a mechanism for gene expression using RNA immunoprecipitation sequencing. Analysis reveals that neuronal activity changes U1 snRNP binding to ~2000 transcripts and for a subset of transcripts, a reduction in U1 snRNP binding was accompanied by utilization of a cryptic intronic polyadenylation site. This subset is enriched for transcripts encoding synaptic proteins involved in excitability control. Genes demonstrating activity-dependent reduced U1 snRNP binding often encode a binding motif for Sam68, a neuronal alternative polyadenylation factor. Findings reveal that activity-driven changes in intron utilization for transcript termination serves an important role in synaptic plasticity.

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