Abstract
microRNAs (miRNAs) repress target transcripts through partial complementarity. By contrast, highly complementary miRNA-binding sites within viral and artificially engineered transcripts induce miRNA degradation in vitro and in cell lines. Here, we show that a genome-encoded transcript harboring a near-perfect and deeply conserved miRNA-binding site for miR-29 controls zebrafish and mouse behavior. This transcript originated in basal vertebrates as a long noncoding RNA (lncRNA) and evolved to the protein-coding gene NREP in mammals, where the miR-29-binding site is located within the 3′ UTR. We show that the near-perfect miRNA site selectively triggers miR-29b destabilization through 3′ trimming and restricts its spatial expression in the cerebellum. Genetic disruption of the miR-29 site within mouse Nrep results in ectopic expression of cerebellar miR-29b and impaired coordination and motor learning. Thus, we demonstrate an endogenous target-RNA-directed miRNA degradation event and its requirement for animal behavior.
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Acknowledgements
We thank R. Pillai and E. Heard for comments on this manuscript. We also thank all members of the Shkumatava lab for useful discussions and B. Foret and A.-V. Gendrel of the E. Heard lab for advice on ESC differentiation. This work was supported by grants from ERC (FLAME-337440), ATIP-Avenir, La Fondation Bettencourt Schueller and La Fondation pour la Recherche Médicale (FRM DBI201312285578) to A.S. The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. GA 310206 to D.O’C and the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) grant agreement no. 602805 to W.H.J.N. High-throughput sequencing was performed by the ICGex NGS platform of the Institut Curie, supported by the grants ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09-08 (France Génomique Consortium) from the Agence Nationale de la Recherche (“Investissements d’Avenir” program), by the Canceropole Ile-de-France and by the SiRIC-Curie program - SiRIC Grant INCa-DGOS- 4654.
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A.B. and A.C.M. contributed to the design, execution and analysis of most of the experiments. C.C. contributed to the design, generation and execution of the NrepmiR-29scr allele. E.G. and S.M. performed and analyzed mouse behavioral experiments. H.C.G., W.H.J.N. and A.B. performed and analyzed zebrafish behavioral experiments. E.P. performed the in situ hybridization staining. Y.A.P.-R. performed the phylogenetic and sequence conservation analyses. G.P.T.-V. and D.O’C. thought of the NrepmiR-29scr allele. A.J.E. performed the bioinformatics analyses of small-RNA sequencing. A.S. conceived the study. D.O’C. and A.S. supervised the study. A.S. and A.C.M. wrote the final version of the manuscript.
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Supplementary Figure 1 Conservation of the libra, Nrep and miR-29 sequences.
(a) Conservation of the miR-29 site and its flanking sequences. The sequence logo based on 30 homologous sequences is shown above representative examples from the indicated species. Asterisks indicate bases conserved in all of the representative examples. The miR-29 site is in blue and underlined. (b) Predicted Nrep pairing with the individual mouse miR-29 family members. Watson-Crick paired nucleotides are in black and connected by vertical lines, whereas wobbled paired nucleotides are in blue. (c) Multiple alignment of the NREP ORF across vertebrates. Amino acids conserved in all species are in blue. An asterisk indicates a putative stop codon. (d) Unrooted consensus Bayesian phylogenetic tree of zebrafish libra and its homologs in 24 vertebrate species. Branch lengths represent the number of substitutions per site as indicated in the scale bar. Posterior probabilities for all branch splits are displayed in the nodes. (e) The miR-29 family members of zebrafish (a and b) and human and mouse (a, b and c). The seed sequence is boxed, bases differing among the individual miR-29s are in red. (f) libra, miR-29a and miR-29b show partially overlapping expression detected by in situ hybridization on adult zebrafish brain sections. Representative sections for each probe are shown (wild-type animals, n=6). Telencephalon (Tel), Tectum opticum (TeO), Corpus Cerebelli (CCe), Medulla Oblongata (MO), Inferior Lobe (IL). (g) Control in situ hybridization on zebrafish adult brain sections using scrambled miRNA probes. (h) Control in situ hybridization on mouse adult brain sections using scrambled miRNA probes. The brain section is outlined with a dashed line. Representative sections for each probe are shown (wild-type zebrafish, n=6 and mouse, n=4).
Supplementary Figure 2 Generation and validation of the libradel and librainv zebrafish mutants.
(a) The libradel zebrafish locus showing the positions of the sgRNA Guide 1 and Guide 2 used to generate the libradel mutant. The nucleotides defining the borders of the deleted genomic sequence block are shown in gray and delineated by red arrowheads. The short guide and PAM sequences are indicated with blue and pink blocks, respectively. (b) The librainv zebrafish locus showing the positions of the sgRNA Guide 2 and Guide 3 used to generate the librainv mutant and the inverted portion of exon 3 (hashed block). The nucleotides defining the borders of the inverted part of the libra transcript in the librainv mutant are indicated in lavender and delineated by red arrowheads. The short guide and PAM sequences are indicated with blue and pink blocks, respectively. (c) Generation of the libradel and librainv alleles was confirmed by RNA-Seq. The positions of the libra locus together with that of the adjacent annotated upstream and downstream loci are indicated, and the corresponding H3K4me3 ChIP-Seq, 3P-Seq and RNA-Seq tracks from wild type, libradel and librainv zebrafish are shown. The y-axis of the RNA-Seq tracks represents raw read counts. The inverted portion of the libra transcript in librainv mutant is indicated in lavender.
Supplementary Figure 3 Behavior of the libradel and librainv zebrafish mutants.
(a) The number (n) of entries, (b) time in seconds (s) spent near the novel object testing boldness and (c) latency to approach the novel object in seconds (s) of wild type and libra mutants. Each dot represents an individual adult fish from one experiment; wild-type animals, n=14; libradel animals, n=15; librainv animals, n=15. (d) Velocity in centimeters per second (cm/s), (e) total distance swum in centimeters (cm) and (f) time in seconds (s) spent at the aggressive display recorded in the aggression test for the indicated genotypes. Each dot represents an individual adult fish from one experiment; wild-type animals, n=12; libradel animals, n=15; librainv animals, n=14; **P < 0.01; n.s., not significant. Data are presented as mean ± s.e.m., One-way ANOVA and Dunnett’s multiple comparisons tests were performed for all analyses except for latency to approach the novel object where Kruskal-Wallis and Dunn’s multiple comparisons tests were performed. The novel-object boldness and aggression tests were each performed in one experiment. Detailed statistical analyses and source data are provided in Supplementary Table 1 and Supplementary Dataset 2.
Supplementary Figure 4 Generation and expression analyses of the mouse NrepmiR-29scr allele.
(a) The mouse Nrep locus showing the positions of the sgRNA Guide 4 and Guide 5 used to generate the NrepmiR-29scr mutant mice. The short guide and PAM sequences are indicated with blue and pink blocks, respectively. The wild-type and scrambled miR-29 site is highlighted in green, and the scrambled nucleotides are in red. A BamHI restriction site was introduced to facilitate mutant screening. (b) Hematoxylin and eosin staining of brain sections from wild-type (left) and NrepmiR-29scr (right) mice. Upper panel, whole brain; bottom panel, zoom-in of the cerebellum. Scale bars represent 50 µm. Representative sections for the indicated genotype are shown (wild-type animals, n=4; NrepmiR-29scr animals, n=4). Cortex (Cx), Striatum (Str), Hippocampus (Hip), Thalamus (Thal), Cerebellum (Cb). (c) qRT-PCR analysis of Nrep expression in the cerebellum of wild-type (blue) and NrepmiR-29scr (purple) mutant mice (wild-type animals, n=6; NrepmiR-29scr animals, n=5). Gapdh was used as a reference gene. Data are presented as mean ± s.e.m.; unpaired t-test: n.s., not significant at 95% confidence level. Detailed statistical analyses and source data for panel c are provided in Supplementary Table 1 and Supplementary Dataset 2.
Supplementary Figure 5 Behavior of NrepmiR-29scr mice.
(a) Work flow of the three phases of the contextual and cued fear conditioning test. (b) Number of activity counts before shock in the fear conditioning test; wild-type (WT) animals, n=16; NrepmiR-29scr animals, n=15. Data are presented as individual data points and mean ± s.e.m. (c-e) Number of freezing episodes of NrepmiR-29scr (purple) and wild type (blue) mice in the fear conditioning test presented in 1 min intervals during (c) the conditioning session (arrows indicate the time of the CS + foot-shock application); (d) the context session; (e) the cue session (CS presented during min 3-4 and 7-8). Wild-type animals, n=14; NrepmiR-29scr animals, n=12. Data are presented as mean ± s.e.m. (f-g) Elevated plus maze test to assess anxiety-related behavior in NrepmiR-29scr (purple) and wild-type (blue) mice. (f) frequency of total arm entries; wild-type animals, n=15; NrepmiR-29scr animals, n=15; and (g) percent time spent in open arms; wild-type animals, n=15; NrepmiR-29scr animals, n=13. Data are presented as individual data points and mean ± s.e.m. Detailed statistical analyses and source data for panels b-g are provided in Supplementary Table 1 and Supplementary Dataset 2.
Supplementary Figure 6 Molecular characterization of NrepmiR-29scr cell lines.
(a) Nrep and miR-29a, b and c expression in wild-type and NrepmiR-29scr ESCs and NPCs detected by RNA blots. The NPC portion of this blot is also shown in Fig. 5a. Three biological replicates are shown for each genotype, technical triplicates were performed for miR-29b and technical duplicates were performed for Nrep, miR-29a and miR-29c. 18S rRNA and U6 RNAs were used as loading references. Uncropped blot images are shown in Supplementary Dataset 1. (b) qRT-PCR analysis of Oct4 and Nestin expression in wild-type and NrepmiR-29scr ESCs and NPCs. Each dot represents an individual biological replicate ESC or NPC population. qRT-PCRs for each biological replicate were performed in technical triplicate. Gapdh was used as a reference gene. Data are presented as mean ± s.e.m.; unpaired t-test: n.s., not significant at 95% confidence level. (c) qRT-PCR analysis of Nrep expression in wild-type and NrepmiR-29scr NPCs. Each dot represents an individual biological replicate NPC population. qRT-PCRs for each biological replicate were performed in technical triplicate. Gapdh was used as a reference gene. Data are presented as mean ± s.e.m.; unpaired t-test: n.s., not significant at 95% confidence level. (d) qRT-PCR analysis of pri-miR-29 expression in wild type and NrepmiR-29scr NPCs. Each dot represents an individual biological replicate NPC population. β-actin was used as a reference gene. Data are presented as mean ± s.e.m.; unpaired t-test: n.s., not significant at 95% confidence level (e) Normalized expression of miR-29 star sequences from small RNA sequencing reads. Each bar represents an individual biological replicate NPC population; unpaired t-test: n.s., not significant. (f) The proportion of small RNA sequencing reads with coverage of at least n indicated nucleotides (nt) along the length of the top five most abundant NPC mmu-miRNAs (miR-21a, let-7i, let-7f, miR-148a and miR-9). For each miRNA, the canonical length and regions tested for trimming and tailing are delineated. Five nucleotides either side of the canonical length were used to test for significant differences in the mean values over these positions using a paired t-test for difference of means. Three biological replicates are shown for each genotype. n.s., not significant at 95% confidence level. Detailed statistical analyses and source data for panels b-f are provided in Supplementary Table 1 and Supplementary Dataset 2.
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Supplementary Figures 1–6, Supplementary Tables 2 and 3 and Supplementary Notes 1–3
Supplementary Dataset 1
Uncropped RNA blots
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Bitetti, A., Mallory, A.C., Golini, E. et al. MicroRNA degradation by a conserved target RNA regulates animal behavior. Nat Struct Mol Biol 25, 244–251 (2018). https://doi.org/10.1038/s41594-018-0032-x
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DOI: https://doi.org/10.1038/s41594-018-0032-x
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