The interplay of active and repressive histone modifications is assumed to have a key role in the regulation of gene expression. In contrast to this generally accepted view, we show that the transcription of genes temporally regulated during fly and worm development occurs in the absence of canonically active histone modifications. Conversely, strong chromatin marking is related to transcriptional and post-transcriptional stability, an association that we also observe in mammals. Our results support a model in which chromatin marking is associated with the stable production of RNA, whereas unmarked chromatin would permit rapid gene activation and deactivation during development. In the latter case, regulation by transcription factors would have a comparatively more important regulatory role than chromatin marks.
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We thank D. Gonzalez-Knowles, A. Breschi and M. Melé for help with data analysis, F. Serras, M. Morey and A. Kornblihtt for insightful suggestions and G. Cavalli for discussing data before publication, as well as the anonymous reviewers for their critical input. We thank R. Garrido for administrative assistance. We thank the modENCODE project, the ENCODE Project (human and mouse data) and the Roadmap Epigenomics Mapping Consortium for granting open access of these resources to the scientific community. We also thank the Ultrasequencing Unit of the Centre for Genomic Regulation (CRG, Barcelona, Spain) for sample processing and the Confocal Unit of CCiTUB (Centres Científics i Tecnològics de la Universitat de Barcelona) (Universitat de Barcelona, Barcelona, Spain). This work was performed under the financial support of the Spanish Ministry of Economy and Competitiveness with grants BIO2011-26205 to R.G., CSD2007-00008 and BFU2012-36888 to M.C., and 'Centro de Excelencia Severo Ochoa 2013–2017', SEV-2012-0208 and the European Research Council/European Community's Seventh Framework Programme with grant 294653 RNA-MAPS to R.G. E.B. is supported by the European Commission's Seventh Framework Programme 4DCellFate grant 277899. This research reflects only the authors' views, and the Community is not liable for any use that may be made of the information contained therein. J.C. is supported by grant SFRH/BD/33535/2008 from the Portuguese Foundation of Science and Technology.
The authors declare no competing financial interests.
Integrated supplementary information
(a) Time points selected for the analysis of chromatin marking in genes regulated during fly development. From the available modENCODE RNA-seq data, we selected the 12 points for which ChIP-seq experiments on histone modifications were also available. (b) Expression of one stable gene (NUCB1) and one regulated gene (Cy30401). The value of the coefficient of variation for NUCB1 is 0.15. Cy30401, in contrast, shows a peak of expression in one embryonic stage, and its coefficient of variation is consistently 2.49. (c) Distribution of the coefficients of variation on fly genes. We calculated the coefficients of variation of expression for the 12,867 genes for which modENCODE has expression data along Drosophila development. The coefficient of variation distribution uncovers a large class of genes with low coefficients of variation (constant expression during development) and two other minor classes containing genes whose expression is highly variable during development—often restricted to a limited set of stages. For most of the analysis, we arbitrarily considered the top 1,000 genes with the lowest coefficients of variation as stable and, the top 1,000 genes with the highest coefficients of variation as genes regulated throughout development (Supplementary Fig. 4). (d) Time point of maximum expression of regulated genes.
Supplementary Figure 2 Chromatin marking at stable, regulated and silent genes during fly development.
We performed a number of controls to rule out the possibility that our observations arose from undetected confounding factors. (a) Normalized levels of H3K4me3, H3K9ac, H3K4me1, H3K27ac, H3K27me3 and H3K9me3 at the time point of maximum expression during development. Because of the differences in heights between modENCODE ChIP-seq tracks, we identified the highest peak of each mark in the genome by checking all expressed genes and used this value to normalize the corresponding profiles. The distributions correspond to the maximum height of the ChIP-seq peak within the gene body for H3K4me3, H3K9ac, H3K4me1 and H3K27ac and the average height of the ChIP-seq signal over the gene body for H3K27me3 and H3K9me3. Patterns are the same or even stronger than those in Figure 1b. The bottom and top of the boxes are the first and third quartiles, and the line within is the median. The whiskers denote the interval within 1.5 times the IQR from the median. Outliers are plotted as dots. (b) Distribution of expression of the top 1,000 stable, regulated and silent genes and of the set of the top 1,000 regulated genes divided into 3 groups according to expression (low, medium, high) at the time point of maximum expression for each gene. Gene expression was computed as FPKM by the modENCODE consortium. (c) Levels of H3K4me3 at the time point of maximum expression for the gene sets defined in b. Values represent the maximum height of the ChIP-seq peak within the gene body. The three sets of regulated genes show similar levels of H3K4me3, comparable to silent genes. (d) Levels of H3K4me3 at the time point of maximum gene expression computed as the average signal over the gene body instead of as the maximum peak. The pattern is the same as that in Figure 1b. (e) Lengths of stable and regulated genes. Regulated genes have a lower number of exons than stable genes (2.6 versus 5.7 on average) and shorter introns (600 bp versus 1,000 bp); as a consequence, regulated genes are shorter than stable genes (1,136 bp versus 2,864 bp). To rule out the possibility that gene size is a confounding factor, we selected the 520 shortest stable genes. These have an average length (1,188 bp) and number of exons (2.6) very similar to those of variable genes. (f) The H3K4me3 maximum peak at short stable genes is comparable to the peak at the previous set of stable genes, and it is much higher than the H3K4me3 peak at regulated genes. Therefore, there is no effect of gene length and number of exons in our observations.
Supplementary Figure 3 Profiles of H3K4me3 along fly development for CG12384, a stable gene, and CG14110, a mid to late embryo-specific gene.
The expression (measured in FPKM) along these points is given on the left. CG12384 is expressed throughout development, and CG14110 is highly expressed in E12–16 h. In situ hybridization images obtained from BDGP1 correspond to stages 13–16 (9–16 h after egg laying) for both genes.
(a) Distribution of the coefficients of variation on fly genes. The distribution of the coefficients of variation of gene expression along fly development reveals one major class of stable genes (P1) and two minor classes of regulated genes (P2 and P3). (b) Number of genes belonging to each class. (c) Distribution of gene expression levels at the developmental time point of maximum gene expression in each class. Gene expression is measured in FPKM by the modENCODE consortium. The bottom and top of the boxes are the first and third quartiles, and the line within is the median. The whiskers denote the interval within 1.5 times the IQR from the median. Outliers are plotted as dots. (d) Normalized levels of histone modifications at the time point of maximum gene expression in each gene class.
(a) Left, H3K27me3 in stable genes. As expected, most genes do not show H3K27me3. Middle, H3K27me3 in regulated genes. Many genes show either no or very low levels of H3K27me3. Right, H3K27me3 in silent genes. The distribution of H3K27me3 marking is very similar to that observed in regulated genes. (b) Left, H3K9me3 in stable genes. Most of the genes do not show H3K9me3. Middle, H3K9me3 in regulated genes. Many genes show either no or very low levels of H3K9me3. Right, H3K9me3 in silent genes. The distribution of H3K9me3 marking is very similar to that observed in regulated genes. (c) Expression level of regulated genes unmarked and marked with H3K27me3. Marked genes (H3K27me3 (log2) > 0) are expressed at levels similar to those in unmarked genes. The bottom and top of the boxes are the first and third quartiles, and the line within is the median. The whiskers denote the interval within 1.5 times the IQR from the median. Outliers are plotted as dots. (d) Expression levels of regulated genes unmarked and marked with H3K9me3. Marked genes (H3K9me3 (log2) > 0) are slightly more weakly expressed than unmarked genes (P = 0.001).
Supplementary Figure 6 Expression of stable genes, regulated genes broadly expressed at L3, silent genes and stably expressed, tissue-specific genes in six different tissues at L3.
Expression levels, measured in FPKM by the modENCODE consortium, of six different tissues. The expression of stable tissue-specific genes is given for each tissue separately in the following order: carcass, central nervous system, digestive system, fat body, imaginal discs and salivary glands. Regulated, broadly expressed genes show higher expression than stable, tissue-specific genes, even in the tissue in which the latter are expressed, except in imaginal discs. The bottom and top of the boxes are the first and third quartiles, and the line within is the median. The whiskers denote the interval within 1.5 times the IQR from the median. Outliers are plotted as dots.
Supplementary Figure 7 Correlation between histone modifications and transcription stability in flies.
Scatterplots of H3K9ac (a), H3K4me1 (b) and H3K27ac (c) at the time point of highest expression during fly development and transcriptional stability, measured as the coefficient of variation in gene expression across the 12 developmental time points. The correlation is computed as the partial correlation given gene expression (Fig. 3b).
Supplementary Figure 8 Chromatin marking at genes with constant and variable expression in multiple tissues in mammals.
(a) Normalized levels of H3K36me3 and H3K4me1 in the tissue with maximum expression from the 56 human consolidated epigenomes. The bottom and top of the boxes are the first and third quartiles, and the line within is the median. The whiskers denote the interval within 1.5 times the IQR from the median. Outliers are plotted as dots. (b) Normalized levels of H3K9ac, H3K36me3, H3K4me1 and H3K27ac in the tissue with maximum expression from the ten mouse tissues.
(a) RNA-seq mapping and quantification statistics. Genomic reads are reads mapping to the genome. Genomic reads mapping uniquely are classified in three classes: intronic reads are reads mapping entirely within a gene but not entirely within annotated exons; exonic reads are reads mapping entirely within exons; and intergenic reads are reads not mapping entirely within genes. Junction reads are reads mapping to splice junctions but not to the genome. (b) Number of genes and transcripts expressed at different expression cutoffs. (c) Mapping statistics for the ChIP-seq experiments on histone modifications. The genome-wide Pearson correlation between the WID and EID epigenomes is very high: 0.90 for H3, 0.84 for H3K4me3, 0.94 for H3K9ac, 0.96 for H3K36me3, 0.92 for H3K4me1 and 0.92 for H3K27ac when computed on the number of reads mapping to 1,000-bp windows. (d,e) Join distribution in WID and EID of gene and transcript expression. Expression is measured in log(RPKM). (f) Gene Ontology term enrichment of 628 genes preferentially expressed in EID and 184 genes preferentially expressed in WID.
(a) Nascent RNA signal computed as the average signal in the gene body for stable, regulated and silent genes in S2 cells2. The bottom and top of the boxes are the first and third quartiles, and the line within is the median. The whiskers denote the interval within 1.5 times the IQR from the median. Outliers are plotted as dots. (b) Nucleosome turnover rate as measured by CATCH-IT2 average signal in S2 cells for each gene class. Nucleosome turnover rate is not different between regulated and stable genes (P = 0.61).
Supplementary Figure 11 Profiles of RNA expression, H3 and histone modifications in WID- and EID-specific genes.
(a) The stable gene tio, the regulated WID-specific gene pdm2 and the regulated EID-specific gene CG34244 are expressed at the same level (green tracks and bottom panel). Histone modifications typical of gene activation are observed in tio, whereas the tissue-specific genes lack all of these, even in the tissue in which they are expressed. (b) The stable gene net, the regulated WID-specific gene CG12009 and the regulated EID-specific gene nerfin-1 are expressed at very similar levels (green tracks and bottom panel), but net exhibits histone modifications, whereas the tissue-specific genes lack all of these, even in the tissue in which they are expressed.
Conservation of core promoter sequence. (a) Distribution of PhastCons scores derived from 12 Drosophila species in the promoter sequence (defined as 200 bp upstream of the TSS) of stable and regulated genes. Promoters of regulated genes show stronger sequence conservation than those of stable genes: average PhastCons score of 0.27 in regulated genes and 0.17 in stable genes (P < 2.2 × 10−16). The bottom and top of the boxes are the first and third quartiles, and the line within is the median. The whiskers denote the interval within 1.5 times the IQR from the median. Outliers are plotted as dots. (b) Conservation of transcription factor binding motifs. We identified the predicted binding motifs for transcription factors that have a PhastCons score greater than 0.95 in the promoter sequence of stable and variable genes. Box plots show the distribution of the number of conserved motifs only for promoters that contain at least one prediction (P = 2.217 × 10−6). P values were computed using Wilcoxon test (one-sided).
(a,b) H3 on frequently (red) and infrequently (blue) included exons in WID (a) and EID (b). (c,d) Correlation between exon inclusion and H3 across exon acceptor sites in WID (c) and EID (d).
Supplementary Figures 1–13 and Supplementary Tables 1, 8 and 11. (PDF 2079 kb)
From left to right, the table shows gene ID, official fene symbol, RPKM in WID and RPKM in EID. (XLS 34 kb)
From left to right, the table shows gene ID, official gene symbol, RPKM in WID and RPKM in EID. (XLS 80 kb)
From left to right, the table shows official gene symbol, CG identifier, expression in WID and expression in EID. (XLS 50 kb)
Only the official gene symbol is represented. (XLS 25 kb)
From left to right, the table shows official gene symbol, CG identifier, expression in WID and expression in EID. (XLS 23 kb)
From left to right, the table shows official gene symbol, CG identifier, expression in WID and expression in EID. (XLS 28 kb)
The columns below the yellow caption correspond to exons frequently included in WID, and the columns below the orange caption correspond to exons frequently included in EID. In both cases, the panels depict, from left to right, chromosome, first coordinate, second coordinate, strand and ratio of exon inclusion. (XLS 136 kb)
The columns below the yellow caption correspond to exons infrequently included in WID, and the columns below the orange caption correspond to exons infrequently included in EID. In both cases, the panels depict, from left to right, chromosome, first coordinate, second coordinate, strand and ratio of exon inclusion. (XLS 32 kb)
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Pérez-Lluch, S., Blanco, E., Tilgner, H. et al. Absence of canonical marks of active chromatin in developmentally regulated genes. Nat Genet 47, 1158–1167 (2015). https://doi.org/10.1038/ng.3381
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