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H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells.

Karmodiya K, Krebs AR, Oulad-Abdelghani M, Kimura H, Tora L - BMC Genomics (2012)

Bottom Line: Our study also suggests that a subset of inactive promoters is selectively and specifically enriched for H3K14ac.This observation suggests that histone acetyl transferases (HATs) prime inactive genes by H3K14ac for stimuli dependent activation.In conclusion our study demonstrates a wider role for H3K9ac and H3K14ac in gene regulation than originally thought.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, BP 10142-67404 ILLKIRCH Cedex, CU de Strasbourg, France.

ABSTRACT

Background: Transcription regulation in pluripotent embryonic stem (ES) cells is a complex process that involves multitude of regulatory layers, one of which is post-translational modification of histones. Acetylation of specific lysine residues of histones plays a key role in regulating gene expression.

Results: Here we have investigated the genome-wide occurrence of two histone marks, acetylation of histone H3K9 and K14 (H3K9ac and H3K14ac), in mouse embryonic stem (mES) cells. Genome-wide H3K9ac and H3K14ac show very high correlation between each other as well as with other histone marks (such as H3K4me3) suggesting a coordinated regulation of active histone marks. Moreover, the levels of H3K9ac and H3K14ac directly correlate with the CpG content of the promoters attesting the importance of sequences underlying the specifically modified nucleosomes. Our data provide evidence that H3K9ac and H3K14ac are also present over the previously described bivalent promoters, along with H3K4me3 and H3K27me3. Furthermore, like H3K27ac, H3K9ac and H3K14ac can also differentiate active enhancers from inactive ones. Although, H3K9ac and H3K14ac, a hallmark of gene activation exhibit remarkable correlation over active and bivalent promoters as well as distal regulatory elements, a subset of inactive promoters is selectively enriched for H3K14ac.

Conclusions: Our study suggests that chromatin modifications, such as H3K9ac and H3K14ac, are part of the active promoter state, are present over bivalent promoters and active enhancers and that the extent of H3K9 and H3K14 acetylation could be driven by cis regulatory elements such as CpG content at promoters. Our study also suggests that a subset of inactive promoters is selectively and specifically enriched for H3K14ac. This observation suggests that histone acetyl transferases (HATs) prime inactive genes by H3K14ac for stimuli dependent activation. In conclusion our study demonstrates a wider role for H3K9ac and H3K14ac in gene regulation than originally thought.

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Differential H3K14ac over inactive promoters as compared to H3K9ac. (A) Heatmap representing the correlation between total H3, H3K9ac, H3K14ac, H3K4me3, H3K27ac, H3K27me3 and H3K9me3 around the TSS (-/+ 2 kb). Active promoter marks; H3K14ac, H3K9ac, H3K4me3 and H3K27ac clustered separately (blue square) to form an active promoter chromatin state. Inactive marks (H3K9me3 and H3K27me3) have higher co-occurrence with H3K14ac as compared to H3K9ac (red square) (B) Ratio of H3K14ac/H3K9ac ChIP-seq tag density plotted for active promoters and inactive promoters. Ratio is significantly higher for inactive promoters suggesting that level of H3K14ac is higher over inactive promoters as compared to H3K9ac.
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Figure 6: Differential H3K14ac over inactive promoters as compared to H3K9ac. (A) Heatmap representing the correlation between total H3, H3K9ac, H3K14ac, H3K4me3, H3K27ac, H3K27me3 and H3K9me3 around the TSS (-/+ 2 kb). Active promoter marks; H3K14ac, H3K9ac, H3K4me3 and H3K27ac clustered separately (blue square) to form an active promoter chromatin state. Inactive marks (H3K9me3 and H3K27me3) have higher co-occurrence with H3K14ac as compared to H3K9ac (red square) (B) Ratio of H3K14ac/H3K9ac ChIP-seq tag density plotted for active promoters and inactive promoters. Ratio is significantly higher for inactive promoters suggesting that level of H3K14ac is higher over inactive promoters as compared to H3K9ac.

Mentions: We next analyzed co-localization of the H3K9 and H3K14 acetylation marks with various active and repressive histone modifications. The Pearson correlation coefficient was calculated for these modifications in a window of 2 kb upstream and downstream the TSSs of all the mouse refseq genes (27095). Heatmap of various histone modifications suggest that active histone marks have high correlation and are grouped together for efficient gene expression (Figure6A, blue square). Surprisingly, we observed higher correlation of H3K14ac with various repressive marks, such as H3K27me3 and H3K9me3, when compared to H3K9ac (Figure6A, red square). To further test the association of H3K14ac with inactive marks, H3K27me3 and H3K9me3, we took 7924 inactive genes, which lack Pol II and H3K4me3 (Figure5A) and calculated the ratio of H3K14ac/H3K9ac tag density. The ratio of H3K14ac/H3K9ac is significantly higher over inactive genes as compared to active genes suggesting that H3K14ac is specifically and significantly enriched at inactive genes (Figure6B). In Figure6B we used H3K4me3, Pol II signals distinguish active TSSs from inactive ones. To further strengthen our observations we took the 500 weakest (or not expressed) and the 500 highest expressed gene promoters, but this time based on their expression profiles as calculated from RNA-seq data (kindly provided by the D. Schübeler), and calculated the ratio of H3K9 and H3K14 acetylation tag densities over the least expressed and highly expressed promoters. This analysis again shows that H3K14ac is specifically enriched at the weakest (or inactive) promoters as compared to H3K9ac ( Additional file 8: Figure S7). This in turn suggests that H3K14ac, which is generally considered as a mark of active promoters along with other acetylation marks, can also mark inactive promoters, although to a lesser extent.


H3K9 and H3K14 acetylation co-occur at many gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stem cells.

Karmodiya K, Krebs AR, Oulad-Abdelghani M, Kimura H, Tora L - BMC Genomics (2012)

Differential H3K14ac over inactive promoters as compared to H3K9ac. (A) Heatmap representing the correlation between total H3, H3K9ac, H3K14ac, H3K4me3, H3K27ac, H3K27me3 and H3K9me3 around the TSS (-/+ 2 kb). Active promoter marks; H3K14ac, H3K9ac, H3K4me3 and H3K27ac clustered separately (blue square) to form an active promoter chromatin state. Inactive marks (H3K9me3 and H3K27me3) have higher co-occurrence with H3K14ac as compared to H3K9ac (red square) (B) Ratio of H3K14ac/H3K9ac ChIP-seq tag density plotted for active promoters and inactive promoters. Ratio is significantly higher for inactive promoters suggesting that level of H3K14ac is higher over inactive promoters as compared to H3K9ac.
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Figure 6: Differential H3K14ac over inactive promoters as compared to H3K9ac. (A) Heatmap representing the correlation between total H3, H3K9ac, H3K14ac, H3K4me3, H3K27ac, H3K27me3 and H3K9me3 around the TSS (-/+ 2 kb). Active promoter marks; H3K14ac, H3K9ac, H3K4me3 and H3K27ac clustered separately (blue square) to form an active promoter chromatin state. Inactive marks (H3K9me3 and H3K27me3) have higher co-occurrence with H3K14ac as compared to H3K9ac (red square) (B) Ratio of H3K14ac/H3K9ac ChIP-seq tag density plotted for active promoters and inactive promoters. Ratio is significantly higher for inactive promoters suggesting that level of H3K14ac is higher over inactive promoters as compared to H3K9ac.
Mentions: We next analyzed co-localization of the H3K9 and H3K14 acetylation marks with various active and repressive histone modifications. The Pearson correlation coefficient was calculated for these modifications in a window of 2 kb upstream and downstream the TSSs of all the mouse refseq genes (27095). Heatmap of various histone modifications suggest that active histone marks have high correlation and are grouped together for efficient gene expression (Figure6A, blue square). Surprisingly, we observed higher correlation of H3K14ac with various repressive marks, such as H3K27me3 and H3K9me3, when compared to H3K9ac (Figure6A, red square). To further test the association of H3K14ac with inactive marks, H3K27me3 and H3K9me3, we took 7924 inactive genes, which lack Pol II and H3K4me3 (Figure5A) and calculated the ratio of H3K14ac/H3K9ac tag density. The ratio of H3K14ac/H3K9ac is significantly higher over inactive genes as compared to active genes suggesting that H3K14ac is specifically and significantly enriched at inactive genes (Figure6B). In Figure6B we used H3K4me3, Pol II signals distinguish active TSSs from inactive ones. To further strengthen our observations we took the 500 weakest (or not expressed) and the 500 highest expressed gene promoters, but this time based on their expression profiles as calculated from RNA-seq data (kindly provided by the D. Schübeler), and calculated the ratio of H3K9 and H3K14 acetylation tag densities over the least expressed and highly expressed promoters. This analysis again shows that H3K14ac is specifically enriched at the weakest (or inactive) promoters as compared to H3K9ac ( Additional file 8: Figure S7). This in turn suggests that H3K14ac, which is generally considered as a mark of active promoters along with other acetylation marks, can also mark inactive promoters, although to a lesser extent.

Bottom Line: Our study also suggests that a subset of inactive promoters is selectively and specifically enriched for H3K14ac.This observation suggests that histone acetyl transferases (HATs) prime inactive genes by H3K14ac for stimuli dependent activation.In conclusion our study demonstrates a wider role for H3K9ac and H3K14ac in gene regulation than originally thought.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, BP 10142-67404 ILLKIRCH Cedex, CU de Strasbourg, France.

ABSTRACT

Background: Transcription regulation in pluripotent embryonic stem (ES) cells is a complex process that involves multitude of regulatory layers, one of which is post-translational modification of histones. Acetylation of specific lysine residues of histones plays a key role in regulating gene expression.

Results: Here we have investigated the genome-wide occurrence of two histone marks, acetylation of histone H3K9 and K14 (H3K9ac and H3K14ac), in mouse embryonic stem (mES) cells. Genome-wide H3K9ac and H3K14ac show very high correlation between each other as well as with other histone marks (such as H3K4me3) suggesting a coordinated regulation of active histone marks. Moreover, the levels of H3K9ac and H3K14ac directly correlate with the CpG content of the promoters attesting the importance of sequences underlying the specifically modified nucleosomes. Our data provide evidence that H3K9ac and H3K14ac are also present over the previously described bivalent promoters, along with H3K4me3 and H3K27me3. Furthermore, like H3K27ac, H3K9ac and H3K14ac can also differentiate active enhancers from inactive ones. Although, H3K9ac and H3K14ac, a hallmark of gene activation exhibit remarkable correlation over active and bivalent promoters as well as distal regulatory elements, a subset of inactive promoters is selectively enriched for H3K14ac.

Conclusions: Our study suggests that chromatin modifications, such as H3K9ac and H3K14ac, are part of the active promoter state, are present over bivalent promoters and active enhancers and that the extent of H3K9 and H3K14 acetylation could be driven by cis regulatory elements such as CpG content at promoters. Our study also suggests that a subset of inactive promoters is selectively and specifically enriched for H3K14ac. This observation suggests that histone acetyl transferases (HATs) prime inactive genes by H3K14ac for stimuli dependent activation. In conclusion our study demonstrates a wider role for H3K9ac and H3K14ac in gene regulation than originally thought.

Show MeSH