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Genome-wide identification of endogenous NMD-targeted RNAs in human stem cells [UPF2_NPCs]

ABSTRACT: Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that influences several biological processes. Specific features in messenger RNAs (mRNAs) have been found to trigger decay by NMD, leading to the assumption that NMD sensitivity is an intrinsic quality of a given transcript. Here, we provide evidence that, instead, an overriding factor dictating NMD sensitivity is the cell environment. Using several genome-wide techniques to detect NMD-target mRNAs, we find that hundreds of mRNAs are sensitized to NMD as human embryonic stem cells progress to form neural progenitor cells. Another class of mRNAs escape from NMD during this developmental progression. We show that the differential sensitivity to NMD extends to in vivo scenarios, and that the RNA-binding protein, HNRNPL, has a role in cell type-specific NMD. We also addressed another issue in the field-whether NMD factors are core or branch-specific in their action. Surprisingly, we found that UPF3B, an NMD factor critical for the nervous system, shares only 30% of NMD-target transcripts with the core NMD factor UPF2. Together, our findings have implications for how NMD is defined and measured, how NMD acts in different biological contexts, and how different NMD branches influence human diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263403 | GEO | 2025/05/21

REPOSITORIES: GEO

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Genome-wide identification of endogenous NMD-targeted RNAs in human stem cells [UPF3B_ESCs]

Project description:Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that influences several biological processes. Specific features in messenger RNAs (mRNAs) have been found to trigger decay by NMD, leading to the assumption that NMD sensitivity is an intrinsic quality of a given transcript. Here, we provide evidence that, instead, an overriding factor dictating NMD sensitivity is the cell environment. Using several genome-wide techniques to detect NMD-target mRNAs, we find that hundreds of mRNAs are sensitized to NMD as human embryonic stem cells progress to form neural progenitor cells. Another class of mRNAs escape from NMD during this developmental progression. We show that the differential sensitivity to NMD extends to in vivo scenarios, and that the RNA-binding protein, HNRNPL, has a role in cell type-specific NMD. We also addressed another issue in the field-whether NMD factors are core or branch-specific in their action. Surprisingly, we found that UPF3B, an NMD factor critical for the nervous system, shares only 30% of NMD-target transcripts with the core NMD factor UPF2. Together, our findings have implications for how NMD is defined and measured, how NMD acts in different biological contexts, and how different NMD branches influence human diseases.

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Deciphering the cellular roles and dissecting functional regions of UPF3A and UPF3B in human NMD

Project description:The paralogous proteins UPF3A and UPF3B are involved in recognizing defective mRNAs that are degraded by nonsense-mediated mRNA decay (NMD). While UPF3B has been demonstrated to support NMD, UPF3A was reported to act either an NMD activator or an NMD inhibitor. Here, we present a comprehensive functional analysis of UPF3A and UPF3B in human cells using overexpression, knockdowns, knockouts (KO) and rescue experiments. Overexpression or knockout of UPF3A did not result in detectable changes in global NMD activity or other specific transcriptome alterations . NMD activity was also virtually unchanged in UPF3B KO cells. In contrast, the co-depletion or co-knockout of UPF3A and UPF3B resulted in a marked NMD inhibition and a global upregulation of PTC-containing transcripts. In rescue experiments UPF3B was fully functional when either UPF2- or EJC binding was impaired . However, the deletion of both interaction sites or one interaction site and a central region of UPF3B impaired its NMD function. Altogether, our work identifies critical functional domains of UPF3B and establishes redundant roles of UPF3A and UPF3B during NMD.

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Dosage imbalance of NMD genes is associated with intellectual disability

Project description:Nonsense-mediated mRNA decay (NMD) functions to degrade transcripts bearing premature stop codon (PTC) and is a crucial regulator of gene expression. NMD and the UPF3B gene have been implicated as the cause of various forms of intellectual disability (ID) and other neurological symptoms. Here, we reports three patients with global developmental delay carrying hemizygous deletions of the UPF2 gene, another important member of the NMD pathway and direct interacting partner of UPF3B. Using RNA-SEQ on lymphoblastoid cells from UPF2 deletion patients, we identified 1009 differently expressed genes (DEGs). 38% of these DEGs overlapped with DEGs identified in UPF3B patients. More importantly, 95% of all DEGs in either UPF2 or UPF3B patients share the same trend of de-regulation. This demonstrates that the transcriptome deregulation in these two patient groups is similar and that UPF2 should be considered as a new candidate gene for ID in man. We expanded our inq`uiries and performed a comprehensive search for copy number variations (CNVs) encompassing all NMD genes in cohorts of ID patients and controls. We found that UPF2, UPF3A, Y14, SMG6 and EIF4A3 are frequently deleted and/or duplicated in ID patients. These CNVs are likely to be the root of the problems or to act as predisposing factors. Our results suggest that dosage imbalance of NMD factors is associated with ID and further emphasize the importance of NMD in normal learning and memory processes.

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Project description:Nonsense-mediated decay (NMD) is an evolutionarily conserved surveillance mechanism that targets mRNAs undergoing premature translation termination for rapid degradation as well as normal physiological transcripts. From yeast to humans, NMD requires the function of three conserved Up-frameshift (Upf) factors (Upf1, Upf2, Upf3). Interestingly, in humans, mutations in UPF2 and UPF3B are associated with intellectual disability and autism spectrum disorder (ASD). However, the neurobiological mechanism by which deficient NMD leads to neurodevelopmental disorders remains unknown. Consequently, no treatment is currently available. Here we report that mice lacking Upf2 in the murine forebrain (Upf2 fb-KO mice) show endophenotypes associated with ASD and deficits in learning and memory. In addition, Upf2-mediated deficient NMD leads to abnormal long-term potentiation (LTP) in the hippocampus. Like patients with mutations in UPF2, Upf2 fb-KO mice showed neuroanatomical abnormalities including a smaller corpus callosum. Surprisingly, transcriptomic analysis revealed elevated mRNA expression of immune-related genes in the hippocampus of Upf2-fb-KO mice, which was accompanied by increased inflammation and progressive infiltration of peripheral immune cells. More importantly, treatment with an FDA-approved immunosuppressant, cyclophosphamide (CyP), significantly reduces brain inflammation, improves the neuroanatomical defects and the deficits in LTP and memory deficits, and reverses some of the ASD-like behaviors, notably the social deficits. Collectively, our results reveal the biological basis underlying neurodevelopmental disorders associated with dysfunctional NMD. Moreover, these findings suggest that immunosuppressant drugs, like CyP, may provide a new therapeutic approach for the treatment of patients with mutations in core NMD components.

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