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Drosophila melanogaster

ABSTRACT: Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for Spinal Muscular Atrophy

PROVIDER: PRJNA320641 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR3476490_1.fastq.gz	Fastqsanger.gz
	SRR3476490_2.fastq.gz	Fastqsanger.gz
	SRR3476500_1.fastq.gz	Fastqsanger.gz
	SRR3476500_2.fastq.gz	Fastqsanger.gz
	SRR3476491_1.fastq.gz	Fastqsanger.gz

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Transcriptomic comparison of Drosophila snRNP biogenesis mutants reveals mutant-specific changes in pre-mRNA processing: implications for Spinal Muscular Atrophy

Project description:RNA-seq analysis of Drosophila snRNP biogenesis mutants. In brief, the Phax and Ars2 mutant RNA-seq was used in combination with Series GSE49587 (Smn mutant and wild-type Oregon-R RNA-seq) to classify transcriptome changes as snRNP-dependent or mutant specific. Additional flies with Smn transgenes, containing Smn mutations that cause Spinal Muscular Atrophy (SMA) in humans, were then used to determine whether the snRNP-dependent or mutant specific changes were present in intermediate models of SMA.

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

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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.

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Expression data in muscle cells (myotubes) of motor neuron disorders (ALS, SBMA, SMA-IV) and healthy controls

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SUMO2 Regulates Histone Pre-mRNA Processing by Stabilizing Histone Locus Body Interactions and Promoting U7 snRNP Assembly

Project description:Histone mRNAs are the only non-polyadenylated mRNAs in eukaryotic cells and require specialized processing in nuclear organelles known as histone locus bodies (HLBs), where essential processing factors are concentrated, including the U7 snRNP complex. Recent studies have revealed that misregulation of histone pre-mRNA processing can lead to polyadenylation of histone mRNAs and disruption of histone protein homeostasis. Despite the links to human disease, the factors contributing to polyadenylation of histone mRNAs and the mechanisms underlying HLB assembly and U7 snRNP biogenesis remain unclear. Here, we report novel functions of the small ubiquitin-related modifier 2 (SUMO2) in regulating histone pre-mRNA processing. Using a SUMO2 knockout osteosarcoma cell line, we identified a defect in 3’ end cleavage and a global increase in histone mRNA polyadenylation. Subsequent analysis of HLBs revealed increased dynamics and reduced levels of the U7 snRNP complex. By over-expressing U7 snRNP-specific components, Lsm11 and U7 snRNA, we partially rescued U7 snRNP levels and processing defects in SUMO2 knockout cells. Through analysis of Lsm11, we identified a SUMO-interacting motif in its N-terminus required for efficient incorporation into U7 snRNP complexes. Collectively, we demonstrate that SUMO2 promotes histone pre-mRNA 3’ end processing through stabilizing HLB interactions and facilitating U7 snRNP assembly

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