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Developmental dynamics of lncRNAs across mammalian organs and species

Abstract

Although many long noncoding RNAs (lncRNAs) have been identified in human and other mammalian genomes, there has been limited systematic functional characterization of these elements. In particular, the contribution of lncRNAs to organ development remains largely unexplored. Here we analyse the expression patterns of lncRNAs across developmental time points in seven major organs, from early organogenesis to adulthood, in seven species (human, rhesus macaque, mouse, rat, rabbit, opossum and chicken). Our analyses identified approximately 15,000 to 35,000 candidate lncRNAs in each species, most of which show species specificity. We characterized the expression patterns of lncRNAs across developmental stages, and found many with dynamic expression patterns across time that show signatures of enrichment for functionality. During development, there is a transition from broadly expressed and conserved lncRNAs towards an increasing number of lineage- and organ-specific lncRNAs. Our study provides a resource of candidate lncRNAs and their patterns of expression and evolutionary conservation across mammalian organ development.

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Acknowledgements

We thank S. Anders, M. Sepp, E. Leushkin and members of the Kaessmann group for discussions, M. Sanchez-Delgado and N. Trost for assistance in figure design, and I. Moreira for help in the development of the interactive tool. We acknowledge support by the state of Baden-Württemberg through bwHPC and the German Research Foundation (DFG) through grant INST 35/1134-1 FUGG. This research was supported by grants from the European Research Council (615253, OntoTransEvol) and Swiss National Science Foundation (146474) to H.K., by the Marie Curie FP7-PEOPLE-2012-IIF to M.C.-M. (329902) and by a scholarship for MSc studies by the Alexander S. Onassis Public Benefit Foundation (F ZL 084-1/2015-2016) to I.S.

Peer review information

Nature thanks Camille Berthelot, Igor Ulitsky and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

M.C.-M. and H.K. conceived and organized the study based on an original design by H.K. R.M. performed the lncRNA annotation and orthology assignment. I.S. performed all other analyses, under the supervision of M.C.-M. and H.K. I.S., M.C.-M. and H.K. wrote the manuscript, with input from R.M.

Competing interests

The authors declare no competing interests.

Correspondence to Margarida Cardoso-Moreira or Henrik Kaessmann.

Extended data figures and tables

Extended Data Fig. 1 Annotation and orthology assignment of lncRNAs.

a, Schematic representation of the lncRNA annotation pipeline. b, Schematic representation of the pipeline for the detection of 1:1 lncRNA families.

Extended Data Fig. 2 Genomic classification and expression patterns of lncRNAs.

a, Distribution of lncRNAs among genomic classes in each species. b, Comparison of genomic classes (left), evolutionary age (middle) and organ of maximum expression (right) for known (Ensembl19) and newly annotated (novel) human lncRNAs. c, Number of species with a detected lncRNA member for human families of various evolutionary ages. d, Comparison of the fraction of species with a detected lncRNA member for human families conserved across mammals (180 Ma) and amniotes (300 Ma) with a previous study8. e, Fraction of lncRNAs and protein-coding gene orthologues found in conserved synteny with at least one protein-coding gene neighbour for increasing evolutionary distances. f, Organ of maximum expression for expressed lncRNAs (≥1 RPKM) in each species. g, Number of lncRNAs expressed (≥1 RPKM) in each species during the development of each organ (in logarithmic scale).

Extended Data Fig. 3 Features of developmentally dynamic lncRNA expression.

a, Representative examples of human developmentally dynamic (n = 5,887) and non-dynamic (n = 25,791) lncRNA expression profiles (mean expression; vertical bars represent the minimum and maximum values across replicates) for varying levels of maximum expression, replicate reproducibility and expression windows. The vertical dashed line represents birth; the horizontal dashed line marks 1 RPKM. b, Summary statistics for the lncRNAs and protein-coding genes in this study. c, Number of organs with developmentally dynamic expression for dynamic lncRNAs and protein-coding genes in each species. d, e, Tissue-specificity (d) and median time-specificity (e) of non-dynamic and dynamic lncRNAs, and protein-coding genes, across species. Tissue- and time-specificity indexes range from 0 (broad expression) to 1 (specific expression). All comparisons between non-dynamic and dynamic lncRNAs, and protein-coding genes are significant (P = 2.2 × 10−16, two-sided Mann–Whitney U-test). f, Maximum expression levels (log10(RPKM)) for developmentally dynamic and non-dynamic lncRNAs across species (excluding samples from the sexually mature testis). Developmentally dynamic lncRNAs are more highly expressed in all species (P = 2.2 × 10−16, two-sided Mann–Whitney U-test). Box plots are as in Fig. 2.

Extended Data Fig. 4 Functionality signature enrichments of developmentally dynamic lncRNAs.

a, Fraction of developmentally dynamic human lncRNAs (n = 5,887) for different genomic classes. Overrepresented classes were determined by comparing the fraction of dynamic lncRNAs in each class against all other classes. b, Normalized density distribution of the distance to the nearest protein-coding gene for dynamic (n = 5,887) and non-dynamic (n = 25,791) human lncRNAs. c, Generation of expression-matched dynamic (n = 2,906) and non-dynamic (n = 3,098) lncRNAs and their distribution among genomic classes. d, Fraction of developmentally dynamic human lncRNAs among isoforms with an increasing number of exons. The number of exons is significantly higher for developmentally dynamic lncRNAs (P = 2.2 × 10−16, two-sided Mann–Whitney U-test). e, Fraction of human lncRNAs that are intergenic, developmentally dynamic and that do not overlap enhancers25 (n = 16,481) among different age groups. f, Fraction of developmentally dynamic genes across expression-matched (n = 6,004) human lncRNAs of different age groups (top) and functionally characterized lncRNAs27 (bottom). g, Generation of expression-matched, lowly expressed (0.25–0.75 RPKM) dynamic (n = 798) and non-dynamic (n = 717) human lncRNAs and their distribution across different age groups. h, Fraction of developmentally dynamic human lncRNAs (n = 5,887) with or without a mouse (dynamic or not) orthologue (P = 2.2 × 10−16, Fisher’s exact test). i, Similarity of spatiotemporal expression (Spearman correlation coefficient between human and mouse organs/developmental stages) for 1:1 orthologues. j, Expression similarity across matched organs and developmental stages for mouse and rat 1:1 orthologous lncRNAs that are dynamic in both species, for different evolutionary ages. k, Fraction of lncRNAs present in the CRISPRi screen library21 resulting in a significant growth phenotype (hits) in at least one cell line for lncRNAs present (n = 2,364) or absent (n = 14,037) in our annotation and dynamic (n = 1,093) or non-dynamic (n = 1,277). l, Fraction of lncRNAs present in the CRISPRi screen library21 resulting in a significant growth phenotype (hits) in expression-matched dynamic (n = 2,906) and non-dynamic lncRNAs (n = 3,098). Box plots are as in Fig. 2. In al, statistical tests are two-sided.

Extended Data Fig. 5 Transcriptional regulation of dynamic lncRNAs in mouse.

a, Fraction of promoters of protein-coding genes, dynamic and non-dynamic lncRNAs, and size-matched random intergenic regions that overlap with binding sites for TFs. Each data point corresponds to a TF (n = 355). Box plots are as in Fig. 2. b, Selection of the 50 TFs with the highest binding variability across promoters of lncRNAs that were dynamic in different organs (in blue). TFs with maximum binding frequency ≤ 0.05 (red line) were not considered, as their high variability is probably associated with a low binding frequency. c, Spatiotemporal expression patterns of the 50 most variable TFs in mouse. The heat map is clustered by rows and shows expression levels in counts (after variance-stabilizing transformation).

Extended Data Fig. 6 Patterns of lncRNA expression in mammalian development.

a, Number of differentially expressed protein-coding genes and dynamic lncRNAs between adjacent stages of organ development in human, rat, rabbit, opossum and chicken. b, Number of differentially expressed ‘isolated intergenic’ (more than 100 kb from the closest protein-coding-gene) dynamic lncRNAs between adjacent stages during mouse development.

Extended Data Fig. 7 Clustering of dynamic lncRNAs based on developmental trajectories.

Clusters of developmentally dynamic lncRNAs and protein-coding genes across mouse organs (brain = 14,629 genes; cerebellum = 13,166; heart = 12,382; kidney = 14,634; liver = 13,888; ovary = 12,694; testis = 13,749). Grey lines represent individual gene trajectories and solid lines posterior mean trajectories for each cluster. Clusters are arranged by decreasing fraction of lncRNAs. Enriched representative biological processes (Benjamini–Hochberg adjusted P < 0.05, hypergeometric test) are shown for each cluster.

Extended Data Fig. 8 Characteristics of dynamic lncRNAs expressed in different developmental stages.

a, Expression similarity between human and mouse 1:1 orthologous protein-coding genes (n = 16,078), developmentally dynamic (n = 281) and non-dynamic (n = 1,386) lncRNAs across organs/developmental stages. Each point corresponds to the Spearman correlation coefficient of expression between human and mouse orthologues for matching samples. Lines and the 95% confidence interval (shaded regions) correspond to linear model predictions. Spearman correlation coefficients between expression similarity and developmental stage are given for each comparison. b, Expression similarity between dynamic human and mouse orthologous lncRNAs from a, summarized by organ. c, Fraction of conserved (≥80 Ma) dynamic lncRNAs expressed in each mouse organ during development. The colour signifies the focal organ for each comparison. d, Tissue-specificity for mouse lncRNAs with different developmental trajectories. e, Fraction of human lncRNAs with different developmental trajectories among functionally characterized lncRNAs27 (n = 59). f, CRISPRi growth screen hits21 (n = 98). g, Fraction of late-expressed dynamic (n = 2,956) and non-dynamic (n = 25,791) lncRNAs for different age groups and functionally characterized27 human lncRNAs. Box plots are as in Fig. 2. *P < 0.05, **P < 0.01, ***P < 0.001, two-sided Mann–Whitney U-test (bd) or Fisher’s exact test (eg).

Extended Data Fig. 9 Co-expression of dynamic lncRNAs with adjacent protein-coding genes.

a, Normalized density distribution of Pearson correlation coefficients (r) of spatiotemporal gene expression between adjacent paralogous (human = 267; mouse = 263) and non-paralogous (human = 3,359; mouse = 3,382) mRNA–mRNA pairs. b, Number of paralogous (human = 267; mouse = 263) and non-paralogous (human = 3,359; mouse = 3,382) adjacent mRNA–mRNA pairs detected as co-expressed above a range of Pearson’s r cut-offs. c, Relationship between distance and Pearson correlation of expression for lncRNA–mRNA (human = 4,881; mouse = 4,722) and mRNA–mRNA (human = 3,359; mouse = 3,382) pairs. Lines were estimated through LOESS regression and the 95% confidence interval is shown in grey. d, Distribution of Pearson’s r for lncRNA–mRNA and mRNA–mRNA pairs across different distance intervals. Box plots are as in Fig. 2. e, Density distributions of Pearson’s r between a protein-coding gene and its nearest dynamic lncRNA (human = 2,440; mouse = 2,549) and protein-coding gene (human = 1,606; mouse = 1,777) after excluding antisense and divergently transcribed lncRNAs. f, Enriched biological processes among human protein-coding genes with significantly higher expression correlations with their adjacent dynamic lncRNA than with the control protein-coding gene (n = 358; Benjamini–Hochberg adjusted P < 0.01, hypergeometric test; data for mouse are shown in Fig. 4b). In ae, statistical tests are two-sided.

Supplementary information

Reporting Summary

Supplementary Information

This file contains legends for Supplementary Tables 1-16.

Supplementary Tables 1-16

Supplementary Tables 1-16.

Supplementary Data 1

This file contains the lncRNA annotations used in this study in gtf format. Coordinates correspond to the following genome assemblies (human: hg19; rhesus macaque: rheMac3; mouse: mm10; rat: Rnor_5.0; rabbit: OryCun2.0; opossum: monDom5; chicken: Galgal4).

Supplementary Data 2

This file contains expression tables (in RPKM) for lncRNAs, putative new coding genes (denoted with the suffix “.coding”) and Ensembl-annotated transcribed regions that don’t overlap our lncRNAs in the same strand (v75 for human, v77 for all other species).

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Fig. 1: lncRNAs expressed during mammalian organ development.
Fig. 2: Developmentally dynamic lncRNAs are enriched for functional loci.
Fig. 3: Patterns of dynamic lncRNA expression.
Fig. 4: Co-expression with adjacent protein-coding genes.
Extended Data Fig. 1: Annotation and orthology assignment of lncRNAs.
Extended Data Fig. 2: Genomic classification and expression patterns of lncRNAs.
Extended Data Fig. 3: Features of developmentally dynamic lncRNA expression.
Extended Data Fig. 4: Functionality signature enrichments of developmentally dynamic lncRNAs.
Extended Data Fig. 5: Transcriptional regulation of dynamic lncRNAs in mouse.
Extended Data Fig. 6: Patterns of lncRNA expression in mammalian development.
Extended Data Fig. 7: Clustering of dynamic lncRNAs based on developmental trajectories.
Extended Data Fig. 8: Characteristics of dynamic lncRNAs expressed in different developmental stages.
Extended Data Fig. 9: Co-expression of dynamic lncRNAs with adjacent protein-coding genes.

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