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Enhanced transcriptome maps from multiple mouse tissues reveal evolutionary constraint in gene expression.

Pervouchine DD, Djebali S, Breschi A, Davis CA, Barja PP, Dobin A, Tanzer A, Lagarde J, Zaleski C, See LH, Fastuca M, Drenkow J, Wang H, Bussotti G, Pei B, Balasubramanian S, Monlong J, Harmanci A, Gerstein M, Beer MA, Notredame C, Guigó R, Gingeras TR - Nat Commun (2015)

Bottom Line: This core set of genes captures a substantial fraction of the transcriptional output of mammalian cells, and participates in basic functional and structural housekeeping processes common to all cell types.Perturbation of these constrained genes is associated with significant phenotypes including embryonic lethality and cancer.Evolutionary constraint in gene expression levels is not reflected in the conservation of the genomic sequences, but is associated with conserved epigenetic marking, as well as with characteristic post-transcriptional regulatory programme, in which sub-cellular localization and alternative splicing play comparatively large roles.

View Article: PubMed Central - PubMed

Affiliation: 1] Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, Barcelona 08003, Spain [2] Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskie Gory 1-73, 119992 Moscow, Russia.

ABSTRACT
Mice have been a long-standing model for human biology and disease. Here we characterize, by RNA sequencing, the transcriptional profiles of a large and heterogeneous collection of mouse tissues, augmenting the mouse transcriptome with thousands of novel transcript candidates. Comparison with transcriptome profiles in human cell lines reveals substantial conservation of transcriptional programmes, and uncovers a distinct class of genes with levels of expression that have been constrained early in vertebrate evolution. This core set of genes captures a substantial fraction of the transcriptional output of mammalian cells, and participates in basic functional and structural housekeeping processes common to all cell types. Perturbation of these constrained genes is associated with significant phenotypes including embryonic lethality and cancer. Evolutionary constraint in gene expression levels is not reflected in the conservation of the genomic sequences, but is associated with conserved epigenetic marking, as well as with characteristic post-transcriptional regulatory programme, in which sub-cellular localization and alternative splicing play comparatively large roles.

No MeSH data available.


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Conservation of epigenetic marks in constrained genes.(a) Normalized histone modification profiles 1 kb around transcription start site (TSS) for H3K4me3 and H3K27ac, and around the TTS for H3K36me3 in constrained and unconstrained genes. (b) The difference in normalized average histone modification signals 1 kb around TSS (/Δlog Signal/) in constrained and unconstrained genes. (c) The cumulative distribution of the number of TF ChIP-seq peaks in promoter regions of human constrained and unconstrained genes. (d) Principal component analysis of ChIP-seq measured binding strength of TFs in constrained and unconstrained genes.
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f5: Conservation of epigenetic marks in constrained genes.(a) Normalized histone modification profiles 1 kb around transcription start site (TSS) for H3K4me3 and H3K27ac, and around the TTS for H3K36me3 in constrained and unconstrained genes. (b) The difference in normalized average histone modification signals 1 kb around TSS (/Δlog Signal/) in constrained and unconstrained genes. (c) The cumulative distribution of the number of TF ChIP-seq peaks in promoter regions of human constrained and unconstrained genes. (d) Principal component analysis of ChIP-seq measured binding strength of TFs in constrained and unconstrained genes.

Mentions: Constraint of gene expression is not reflected in sequence conservation of either the gene body or the proximal promoter regions31 (Wilcoxon test, P-value≈0.11 for the difference in phastCons scores; Fig. 4g). In contrast, we found that constrained genes exhibit characteristic patterns of histone modifications, quite divergent from that of unconstrained genes. Using the data collected in these and the human ENCODE studies332 (Supplementary Table 7A,B and Supplementary Methods), we computed genic profiles of normalized histone modification signals, averaging them over all studied cell types (Fig. 5a). We found much stronger signal for active histone modifications (H3K4me3, H3K27ac and H3K36me3) in constrained compared with unconstrained genes. As the set of genes in which we performed the analysis are controlled for differences in gene expression, this is not the result of constrained genes exhibiting higher expression levels. Furthermore, we controlled by gene expression within each sample separately, and found the same effect (Supplementary Fig. 13). Although the association between gene expression and chromatin structure is well known, and models have been developed able to predict gene expression from levels of histone modifications with high accuracy3334, our results suggest that strong chromatin marking is not only associated to high expression levels, but also to high transcription stability across cell types and tissues. This association has been apparently conserved during evolution, since we found that the conservation of the active epigenetic signals is stronger in constrained compared with unconstrained genes (Fig. 5b). These results suggest that constrained and unconstrained genes may be under globally different epigenetic programmes. Further supporting this, we found that constrained genes are regulated by broad promoters (as defined by the FANTOM consortium635) more often than unconstrained genes (67% versus 52%, test of proportions, P-value≈0) that their promoters host more transcription factor (TF) chromatin immunoprecipitation sequencing (ChIP-seq) peaks (using data collected in the ENCODE project7, Supplementary Methods), than unconstrained genes (Fig. 5c), and are slightly depleted in repeat elements at their transcription start site (density of repeat elements in the promoter region 0.82 versus 0.87, Wilcoxon test, P-value≈0.03, Supplementary Methods). Moreover, when performing principal component analysis to classify the promoters of human–mouse orthologous genes based on ChIP-seq measured binding strength of TFs, we found a separation between promoters of constrained and unconstrained genes, although the components capture only a small fraction of the whole variance (Fig. 5d).


Enhanced transcriptome maps from multiple mouse tissues reveal evolutionary constraint in gene expression.

Pervouchine DD, Djebali S, Breschi A, Davis CA, Barja PP, Dobin A, Tanzer A, Lagarde J, Zaleski C, See LH, Fastuca M, Drenkow J, Wang H, Bussotti G, Pei B, Balasubramanian S, Monlong J, Harmanci A, Gerstein M, Beer MA, Notredame C, Guigó R, Gingeras TR - Nat Commun (2015)

Conservation of epigenetic marks in constrained genes.(a) Normalized histone modification profiles 1 kb around transcription start site (TSS) for H3K4me3 and H3K27ac, and around the TTS for H3K36me3 in constrained and unconstrained genes. (b) The difference in normalized average histone modification signals 1 kb around TSS (/Δlog Signal/) in constrained and unconstrained genes. (c) The cumulative distribution of the number of TF ChIP-seq peaks in promoter regions of human constrained and unconstrained genes. (d) Principal component analysis of ChIP-seq measured binding strength of TFs in constrained and unconstrained genes.
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Related In: Results  -  Collection

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f5: Conservation of epigenetic marks in constrained genes.(a) Normalized histone modification profiles 1 kb around transcription start site (TSS) for H3K4me3 and H3K27ac, and around the TTS for H3K36me3 in constrained and unconstrained genes. (b) The difference in normalized average histone modification signals 1 kb around TSS (/Δlog Signal/) in constrained and unconstrained genes. (c) The cumulative distribution of the number of TF ChIP-seq peaks in promoter regions of human constrained and unconstrained genes. (d) Principal component analysis of ChIP-seq measured binding strength of TFs in constrained and unconstrained genes.
Mentions: Constraint of gene expression is not reflected in sequence conservation of either the gene body or the proximal promoter regions31 (Wilcoxon test, P-value≈0.11 for the difference in phastCons scores; Fig. 4g). In contrast, we found that constrained genes exhibit characteristic patterns of histone modifications, quite divergent from that of unconstrained genes. Using the data collected in these and the human ENCODE studies332 (Supplementary Table 7A,B and Supplementary Methods), we computed genic profiles of normalized histone modification signals, averaging them over all studied cell types (Fig. 5a). We found much stronger signal for active histone modifications (H3K4me3, H3K27ac and H3K36me3) in constrained compared with unconstrained genes. As the set of genes in which we performed the analysis are controlled for differences in gene expression, this is not the result of constrained genes exhibiting higher expression levels. Furthermore, we controlled by gene expression within each sample separately, and found the same effect (Supplementary Fig. 13). Although the association between gene expression and chromatin structure is well known, and models have been developed able to predict gene expression from levels of histone modifications with high accuracy3334, our results suggest that strong chromatin marking is not only associated to high expression levels, but also to high transcription stability across cell types and tissues. This association has been apparently conserved during evolution, since we found that the conservation of the active epigenetic signals is stronger in constrained compared with unconstrained genes (Fig. 5b). These results suggest that constrained and unconstrained genes may be under globally different epigenetic programmes. Further supporting this, we found that constrained genes are regulated by broad promoters (as defined by the FANTOM consortium635) more often than unconstrained genes (67% versus 52%, test of proportions, P-value≈0) that their promoters host more transcription factor (TF) chromatin immunoprecipitation sequencing (ChIP-seq) peaks (using data collected in the ENCODE project7, Supplementary Methods), than unconstrained genes (Fig. 5c), and are slightly depleted in repeat elements at their transcription start site (density of repeat elements in the promoter region 0.82 versus 0.87, Wilcoxon test, P-value≈0.03, Supplementary Methods). Moreover, when performing principal component analysis to classify the promoters of human–mouse orthologous genes based on ChIP-seq measured binding strength of TFs, we found a separation between promoters of constrained and unconstrained genes, although the components capture only a small fraction of the whole variance (Fig. 5d).

Bottom Line: This core set of genes captures a substantial fraction of the transcriptional output of mammalian cells, and participates in basic functional and structural housekeeping processes common to all cell types.Perturbation of these constrained genes is associated with significant phenotypes including embryonic lethality and cancer.Evolutionary constraint in gene expression levels is not reflected in the conservation of the genomic sequences, but is associated with conserved epigenetic marking, as well as with characteristic post-transcriptional regulatory programme, in which sub-cellular localization and alternative splicing play comparatively large roles.

View Article: PubMed Central - PubMed

Affiliation: 1] Bioinformatics and Genomics Programme, Centre for Genomic Regulation (CRG) and UPF, Doctor Aiguader, 88, Barcelona 08003, Spain [2] Faculty of Bioengineering and Bioinformatics, Moscow State University, Leninskie Gory 1-73, 119992 Moscow, Russia.

ABSTRACT
Mice have been a long-standing model for human biology and disease. Here we characterize, by RNA sequencing, the transcriptional profiles of a large and heterogeneous collection of mouse tissues, augmenting the mouse transcriptome with thousands of novel transcript candidates. Comparison with transcriptome profiles in human cell lines reveals substantial conservation of transcriptional programmes, and uncovers a distinct class of genes with levels of expression that have been constrained early in vertebrate evolution. This core set of genes captures a substantial fraction of the transcriptional output of mammalian cells, and participates in basic functional and structural housekeeping processes common to all cell types. Perturbation of these constrained genes is associated with significant phenotypes including embryonic lethality and cancer. Evolutionary constraint in gene expression levels is not reflected in the conservation of the genomic sequences, but is associated with conserved epigenetic marking, as well as with characteristic post-transcriptional regulatory programme, in which sub-cellular localization and alternative splicing play comparatively large roles.

No MeSH data available.


Related in: MedlinePlus