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Genome-wide identification of microRNAs regulating the human prion protein.

ABSTRACT: The cellular prion protein (PrP^C ) is best known for its misfolded disease-causing conformer, PrP^Sc . Because the availability of PrP^C is often limiting for prion propagation, understanding its regulation may point to possible therapeutic targets. We sought to determine to what extent the human microRNAome is involved in modulating PrP^C levels through direct or indirect pathways. We probed PrP^C protein levels in cells subjected to a genome-wide library encompassing 2019 miRNA mimics using a robust time-resolved fluorescence-resonance screening assay. Screening was performed in three human neuroectodermal cell lines: U-251 MG, CHP-212 and SH-SY5Y. The three screens yielded 17 overlapping high-confidence miRNA mimic hits, 13 of which were found to regulate PrP^C biosynthesis directly via binding to the PRNP 3'UTR, thereby inducing transcript degradation. The four remaining hits (miR-124-3p, 192-3p, 299-5p and 376b-3p) did not bind either the 3'UTR or CDS of PRNP, and were therefore deemed indirect regulators of PrP^C . Our results show that multiple miRNAs regulate PrP^C levels both directly and indirectly. These findings may have profound implications for prion disease pathogenesis and potentially also for their therapy. Furthermore, the possible role of PrP^C as a mediator of Aβ toxicity suggests that its regulation by miRNAs may also impinge on Alzheimer's disease.

SUBMITTER: Pease D

PROVIDER: S-EPMC8028613 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genome-wide identification of microRNAs regulating the human prion protein.

Pease Daniel D Scheckel Claudia C Schaper Elke E Eckhardt Valeria V Emmenegger Marc M Xenarios Ioannis I Aguzzi Adriano A

Brain pathology (Zurich, Switzerland) 20181221 2

The cellular prion protein (PrPC ) is best known for its misfolded disease-causing conformer, PrPSc . Because the availability of PrPC is often limiting for prion propagation, understanding its regulation may point to possible therapeutic targets. We sought to determine to what extent the human microRNAome is involved in modulating PrPC levels through direct or indirect pathways. We probed PrPC protein levels in cells subjected to a genome-w ...[more]

PMID: 30451334

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Project description:BackgroundMicroRNAs (miRNAs) are small RNAs (sRNAs) approximately 21 nucleotides in length that negatively control gene expression by cleaving or inhibiting the translation of target gene transcripts. Within this context, miRNAs and siRNAs are coming to the forefront as molecular mediators of gene regulation in plant responses to annual temperature cycling and cold stress. For this reason, we chose to identify and characterize the conserved and non-conserved miRNA component of peach (Prunus persica (L.) Batsch) focusing our efforts on both the recently released whole genome sequence of peach and sRNA transcriptome sequences from two tissues representing non-dormant leaves and dormant leaf buds. Conserved and non-conserved miRNAs, and their targets were identified. These sRNA resources were used to identify cold-responsive miRNAs whose gene targets co-localize with previously described QTLs for chilling requirement (CR).ResultsAnalysis of 21 million peach sRNA reads allowed us to identify 157 and 230 conserved and non-conserved miRNA sequences. Among the non-conserved miRNAs, we identified 205 that seem to be specific to peach. Comparative genome analysis between peach and Arabidopsis showed that conserved miRNA families, with the exception of miR5021, are similar in size. Sixteen of these conserved miRNA families are deeply rooted in land plant phylogeny as they are present in mosses and/or lycophytes. Within the other conserved miRNA families, five families (miR1446, miR473, miR479, miR3629, and miR3627) were reported only in tree species (Populustrichocarpa, Citrus trifolia, and Prunus persica). Expression analysis identified several up-regulated or down-regulated miRNAs in winter buds versus young leaves. A search of the peach proteome allowed the prediction of target genes for most of the conserved miRNAs and a large fraction of non-conserved miRNAs. A fraction of predicted targets in peach have not been previously reported in other species. Several conserved and non-conserved miRNAs and miRNA-regulated genes co-localize with Quantitative Trait Loci (QTLs) for chilling requirement (CR-QTL) and bloom date (BD-QTL).ConclusionsIn this work, we identified a large set of conserved and non-conserved miRNAs and describe their evolutionary footprint in angiosperm lineages. Several of these miRNAs were induced in winter buds and co-localized with QTLs for chilling requirement and bloom date thus making their gene targets potential candidates for mediating plant responses to cold stress. Several peach homologs of genes participating in the regulation of vernalization in Arabidopsis were identified as differentially expressed miRNAs targets, potentially linking these gene activities to cold responses in peach dormant buds. The non-conserved miRNAs may regulate cellular, physiological or developmental processes specific to peach and/or other tree species.

Project description:MicroRNAs (miRNAs) are small noncoding RNAs (18-24 nt) and function in many biological processes in plants. Although Eucalyptus trees are widely planted across the world, our understanding of the miRNA regulation in the somatic embryogenesis (SE) of Eucalyptus is still poor. Here we reported, for the first time, the miRNA profiles of differentiated and dedifferentiated tissues of two Eucalyptus species and identified miRNAs involved in SE of Eucalyptus. Stem and tissue culture-induced callus were obtained from the subculture seedlings of E. camaldulensis and E. grandis x urophylla and were used as differentiated and dedifferentiated samples, respectively. Small RNA sequencing generated 304.2 million clean reads for the Eucalyptus samples (n = 3) and identified 888 miRNA precursors (197 known and 691 novel) for Eucalyptus. These miRNAs were mainly distributed in chromosomes Chr03, Chr05, and Chr08 and can produce 46 miRNA clusters. Then, we identified 327 and 343 differentially expressed miRNAs (DEmiRs) in the dedifferentiation process of E. camaldulensis and E. grandis x urophylla, respectively. DEmiRs shared by the two Eucalyptus species might be involved in the development of embryonic callus, such as MIR156, MIR159, MIR160, MIR164, MIR166, MIR169, MIR171, MIR399, and MIR482. Notably, we identified 81 upregulated and 67 downregulated miRNAs specific to E. camaldulensis, which might be associated with the high embryogenic potential. Target prediction and functional analysis showed that they might be involved in longevity regulating and plant hormone signal transduction pathways. Further, using the gene expression profiles, we observed the negative regulation of miRNA-target pairs, such as MIR160~ARF18, MIR396~GRF6, MIR166~ATHB15/HD-ZIP, and MIR156/MIR157~SPL1. Interestingly, transcription factors such as WRKY, MYB, GAMYB, TCP4, and PIL1 were found to be regulated by the DEmiRs. The genes encoding PIL1 and RPS21C, regulated by upregulated miRNAs (e.g., egd-N-miR63-5p, egd-N-miR63-5p, and MIR169,) were downregulated exclusively in the dedifferentiation of E. camaldulensis. This is the first time to study the miRNA regulation in the dedifferentiation process of Eucalyptus and it will provide a valuable resource for future studies. More importantly, it will improve our understanding of miRNA regulation during the somatic embryogenesis of Eucalyptus and benefit the Eucalyptus breeding program.

Dataset Information

Genome-wide identification of microRNAs regulating the human prion protein.

Publications

Genome-wide identification of microRNAs regulating the human prion protein.

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