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Hovlinc is a recently evolved class of ribozyme found in human lncRNA

Nature Chemical Biology volume 17, pages 601–607 (2021)Cite this article

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Abstract

Although naturally occurring catalytic RNA molecules—ribozymes—have attracted a great deal of research interest, very few have been identified in humans. Here, we developed a genome-wide approach to discovering self-cleaving ribozymes and identified a naturally occurring ribozyme in humans. The secondary structure and biochemical properties of this ribozyme indicate that it belongs to an unidentified class of small, self-cleaving ribozymes. The sequence of the ribozyme exhibits a clear evolutionary path, from its appearance between ~130 and ~65 million years ago (Ma), to acquiring self-cleavage activity very recently, ~13–10 Ma, in the common ancestors of humans, chimpanzees and gorillas. The ribozyme appears to be functional in vivo and is embedded within a long noncoding RNA belonging to a class of very long intergenic noncoding RNAs. The presence of a catalytic RNA enzyme in lncRNA creates the possibility that these transcripts could function by carrying catalytic RNA domains.

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Fig. 1: Discovery of the hovlinc ribozyme.
Fig. 2: Biochemical properties of the hovlinc ribozyme.
Fig. 3: RNA structure analysis of the hovlinc ribozyme.
Fig. 4: RNA structure and self-cleavage activity of the minimal functional hovlinc ribozyme (83 nt).
Fig. 5: In vivo activity of the hovlinc ribozyme.

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Data availability

Sequencing data that support the findings of this study have been deposited in GEO with accession number GSE163477. Source data are provided with this paper.

Code availability

Most of the analysis was performed with publicly available software as specified in the main text and Methods. The sequence–structure descriptor files for the corresponding ribozyme types used as input in the RNAMotif program and custom R code used for data processing have been deposited at Github (https://github.com/qifei9/hovlinc_supplements), and are also available at Zenodo (https://doi.org/10.5281/zenodo.4341155).

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Acknowledgements

P.K. thanks the National Natural Science Foundation of China (grant no. 31671382) and the Scientific Research Funds of Huaqiao University. F.Q. thanks the National Natural Science Foundation of China (grant no. 32000462) and the Scientific Research Funds of Huaqiao University. Y.C. thanks the Postgraduates Innovative Fund in Scientific Research from Huaqiao University. K.S.-A. thanks the New York University Abu Dhabi Research Institute and NYUAD Division of Science (funds no. 73 71210 CGSB9 and AD060) for support.

Author information

Author notes

  1. These authors contributed equally: Yue Chen, Fei Qi.

Authors and Affiliations

  1. Institute of Genomics, School of Medicine, Huaqiao University, Xiamen, China

    Yue Chen, Fei Qi, Fan Gao, Huifen Cao, Dongyang Xu & Philipp Kapranov

  2. Division of Science and Math and Center for Genomics and Systems Biology, New York University Abu Dhabi, Abu Dhabi, UAE

    Kourosh Salehi-Ashtiani

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Contributions

P.K. conceived and supervised the project and wrote the manuscript. Y.C. prepared all sequencing libraries, performed all biochemical experiments detecting the in vitro self-cleaving activity of the hovlinc ribozyme, as well as its homologs/mutants under various conditions, and contributed to writing the manuscript. F.Q. analyzed all sequencing data, performed evolutionary and kinetics analysis and contributed to structural analysis of the hovlinc ribozyme and writing the manuscript. F.G. performed experiments addressing the in vivo activity of the hovlinc ribozyme. D.X. contributed to biochemical characterization of the ribozyme. H.C. contributed to the analytical parts at the initial stages of the project. K.S.-A. contributed to the analytical part of the project and to writing the manuscript.

Corresponding authors

Correspondence to Fei Qi or Philipp Kapranov.

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The authors declare no competing interests.

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Peer review information Nature Chemical Biology thanks Andrej Luptak and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Genomic context of the hovlinc ribozyme.

a, Genomic region corresponding to the plus (+) strand vlincRNA containing the hovlinc ribozyme indicated by the dashed lines. The genome annotations from the GENCODE and lncRNA tracks from the UCSC Genome browser are shown. b, Sequences of the 168 nt hovlinc ribozymes in humans and closely related primates. The red triangle represents the cleavage site and the blue triangles mark the boundaries of the 109 nt fragment containing the catalytic core.

Extended Data Fig. 2 Evolutionary process of the hovlinc ribozyme.

a, in mammals. b, in primates. Colors of the names of groups or individual species indicate the presence of homologous sequences (a) or self-cleavage activity (b) (blue: absent, red: present and gray: not included in the analysis). Numbers in the parentheses represent respectively from left to right numbers of species (1) tested for the self-cleavage activity, (2) possessing homologous sequences and (3) included in the evolutionary analysis. The light coral (a) or pale goldenrod (b) boxes indicate the branches that contain sequences either homologous (a) or highly similar (>90% sequence identity) (b) to the human hovlinc ribozyme, respectively. The red circle at the Homininae node shows the deduced first appearance of the self-cleavage activity with subsequent loss in the gorilla branch (blue). Note, several hypotheses for the basal eutherian divergence exist, and this figure is drawn according to the Exafroplacentalia hypothesis21. The phylogenetic trees are simplified for better illustration, and the branches are not drawn to scale.

Extended Data Fig. 3 Sequence identities of the hovlinc ribozyme homologs to the human sequence.

Asterisks mark the prosimians. The dots on top of bars indicate the status of self-cleavage activity (red: active; blue: inactive; and no dot: untested).

Extended Data Fig. 4 Absence of self-cleavage activity in the non-hominin homologs of the hovlinc ribozyme.

The 34 sequences from 40 species representing 20 simians, 5 prosimians and 15 representatives from the other 9 orders covered by our evolutionary analysis were used as templates for IVT. The IVT products were denatured, renatured, and further incubated with either Mg2+ or 1.5 mM EDTA as described in Methods. The only active homologs from chimpanzee and bonobo are shown in Extended Data Fig. 5a,b, respectively. Identical sequences from multiple species were tested only once.

Source data

Extended Data Fig. 5 Activity of different homologs and a sequence variant of the hovlinc ribozyme.

Denaturing PAGE gels with a time course of cleavage reaction for the chimpanzee (a) and bonobo (b) homologs of the hovlinc ribozyme and the human variant containing SNP rs72720496 (c). The cleavage reactions were incubated for the indicated length of time either in the presence of 6 mM Mg2+ or EDTA at pH 8.

Source data

Extended Data Fig. 6 Effect of pH on the hovlinc ribozyme activity.

a−j, The cleavage reactions incubated for the indicated length of time either in the presence of 6 mM Mg2+ or EDTA at the indicated pH were resolved on the denaturing PAGE gels. k, The raw kobs values (in addition to Fig. 2c which plots log kobs values) at different pH. The activity was either negligible or undetectable at pH 6 and 5 respectively. Conditions of pH >10 could not be tested due to RNA degradation.

Source data

Extended Data Fig. 7 Effect of different cations on the hovlinc ribozyme activity.

a, b, d−f, The cleavage reactions incubated for the indicated length of time either in the presence of the indicated cations: Mn2+ (a), Ca2+ (b), Co2+ (d), Co(NH3)63+ (e), Li+ (f) or EDTA at the indicated pH were resolved on the denaturing PAGE gels. c, Time courses of cleavage reactions performed in the presence of various divalent cations at pH 8. Y-axes show the fraction of cleaved products (Ft) for each time point (X-axes). Each symbol represents average Ft from two replicates, and lines represent fitted curves.

Source data

Extended Data Fig. 8 Mutagenesis test of the stem NS in the in silico predicted structure of the hovlinc ribozyme.

a, A predicted structure of the 109 nt fragment that includes the stem NS demarcated by the box. The red triangle indicates the cleavage site. b, PAGE gels and the sequences of the wild type (WT), individual (m) and compensatory (m/m′) mutants of the NS stem. The IVT products were denatured, renatured and further incubated with 6 mM Mg2+ (“+”) or without Mg2+ but with 6 mM EDTA (“−”) at pH 9 as indicated in Methods.

Source data

Extended Data Fig. 9 Activity of the minimal functional hovlinc ribozyme (83 nt).

The cleavage reactions incubated for the indicated length of time at pH 8 (a) and 9 (b) either in the presence of 6 mM Mg2+ or EDTA at the indicated pH were resolved on the denaturing PAGE gels.

Source data

Supplementary information

Supplementary Information

Supplementary Tables 1–4 and the legend for Dataset.

Reporting Summary

Supplementary Dataset

CPM values and ratios for the 3,672 positions common to at least seven of nine libraries.

Source data

Source Data Fig. 1

Unprocessed bioanalyzer electropherogram and PAGE gels for Fig. 1b,d.

Source Data Fig. 1

Statistical source data for Fig. 1c,e.

Source Data Fig. 2

Unprocessed PAGE gels for Fig. 2a.

Source Data Fig. 2

Statistical source data for Fig. 2b−f.

Source Data Fig. 3

Unprocessed PAGE gels for Fig. 3b−h.

Source Data Fig. 4

Unprocessed PAGE gels for Fig. 4a.

Source Data Fig. 4

Statistical source data for Fig. 4c.

Source Data Fig. 5

Statistical source data for Fig. 5b.

Source Data Extended Data Fig. 4

Unprocessed PAGE gels for Extended Data Fig. 4.

Source Data Extended Data Fig. 5

Unprocessed PAGE gels for Extended Data Fig. 5.

Source Data Extended Data Fig. 6

Unprocessed PAGE gels for Extended Data Fig. 6a−j.

Source Data Extended Data Fig. 6

Statistical source for Extended Data Fig. 6k.

Source Data Extended Data Fig. 7

Unprocessed PAGE gels for Extended Data Fig. 7a,b,d−f.

Source Data Extended Data Fig. 7

Statistical source for Extended Data Fig. 7c.

Source Data Extended Data Fig. 8

Unprocessed PAGE gels for Extended Data Fig. 8b.

Source Data Extended Data Fig. 9

Unprocessed PAGE gels for Extended Data Fig. 9a,b.

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Chen, Y., Qi, F., Gao, F. et al. Hovlinc is a recently evolved class of ribozyme found in human lncRNA. Nat Chem Biol 17, 601–607 (2021). https://doi.org/10.1038/s41589-021-00763-0

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