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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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Level of H3K9 and H3K14 acetylation correlates with magnitude of gene expression. A total of 12000 expressed genes in mES cells were divided into ten groups based on their expression levels, from the top 10% (blue, group 1) to the lowest 10% (purple, group 10). Mean tag densities of active histone marks; H3K9ac, H3K14ac, H3K4me3, H3K27ac and Pol II within (-/+) 3 kb are positively correlated with the transcription level of the genes. On the other hand, total H3 densities in the same regions are negatively correlated with the transcription level.
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Figure 2: Level of H3K9 and H3K14 acetylation correlates with magnitude of gene expression. A total of 12000 expressed genes in mES cells were divided into ten groups based on their expression levels, from the top 10% (blue, group 1) to the lowest 10% (purple, group 10). Mean tag densities of active histone marks; H3K9ac, H3K14ac, H3K4me3, H3K27ac and Pol II within (-/+) 3 kb are positively correlated with the transcription level of the genes. On the other hand, total H3 densities in the same regions are negatively correlated with the transcription level.

Mentions: Global transcription is a hallmark of pluripotent ES cells that contributes to plasticity and lineage specification [24]. Histone modifications are known to act in a combinatorial fashion to determine the overall outcome of the gene expression [3]. To explore the correlative relationship between various active histone marks detected at promoters and the transcription of the corresponding genes in mES cells, we compared the level of various active histone marks with the transcriptional level of the genes. Densities of active histone marks (H3K9ac, H3K14ac, H3K4me3 and H3K27ac), as well as total H3 and RNA polymerase II (Pol II), within a 3000 bp window flanking the TSSs of the expressed genes (12100) were collected. All expressed genes [8] were divided into ten categories ranked on the basis of their expression level. Presence of various active histone marks was analyzed over these categories. Analysis of histone H3 occupancy, histone modifications (H3K9ac, H3K14ac, H3K4me3 and H3K27ac) and Pol II around the TSSs suggest that depletion of the total histone H3 signal and enrichment of the active promoter marks (H3K9ac, H3K14ac, H3K4me3 and H3K27ac) at or around TSSs correlate with the increase in gene expression levels. Interestingly, H3K9ac is more spread than the other analyzed active histone marks around the TSSs (Figure2). While Pol II is enriched at or slightly downstream of the TSSs, on these sites the nucleosomes (H3) are depleted (Figure2). This genome-wide observation with various active histone marks is consistent with the notion that H3K9ac and H3K4me3 near the TSSs destabilize interaction between histones and DNA leading to nucleosome eviction [25,26]. Taken together, these results suggest that level of active histone marks (H3K4me3, H3K9ac, H3K14ac and H3K27ac) over the active promoter chromatin state correlates with the magnitude of gene expression.


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)

Level of H3K9 and H3K14 acetylation correlates with magnitude of gene expression. A total of 12000 expressed genes in mES cells were divided into ten groups based on their expression levels, from the top 10% (blue, group 1) to the lowest 10% (purple, group 10). Mean tag densities of active histone marks; H3K9ac, H3K14ac, H3K4me3, H3K27ac and Pol II within (-/+) 3 kb are positively correlated with the transcription level of the genes. On the other hand, total H3 densities in the same regions are negatively correlated with the transcription level.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3473242&req=5

Figure 2: Level of H3K9 and H3K14 acetylation correlates with magnitude of gene expression. A total of 12000 expressed genes in mES cells were divided into ten groups based on their expression levels, from the top 10% (blue, group 1) to the lowest 10% (purple, group 10). Mean tag densities of active histone marks; H3K9ac, H3K14ac, H3K4me3, H3K27ac and Pol II within (-/+) 3 kb are positively correlated with the transcription level of the genes. On the other hand, total H3 densities in the same regions are negatively correlated with the transcription level.
Mentions: Global transcription is a hallmark of pluripotent ES cells that contributes to plasticity and lineage specification [24]. Histone modifications are known to act in a combinatorial fashion to determine the overall outcome of the gene expression [3]. To explore the correlative relationship between various active histone marks detected at promoters and the transcription of the corresponding genes in mES cells, we compared the level of various active histone marks with the transcriptional level of the genes. Densities of active histone marks (H3K9ac, H3K14ac, H3K4me3 and H3K27ac), as well as total H3 and RNA polymerase II (Pol II), within a 3000 bp window flanking the TSSs of the expressed genes (12100) were collected. All expressed genes [8] were divided into ten categories ranked on the basis of their expression level. Presence of various active histone marks was analyzed over these categories. Analysis of histone H3 occupancy, histone modifications (H3K9ac, H3K14ac, H3K4me3 and H3K27ac) and Pol II around the TSSs suggest that depletion of the total histone H3 signal and enrichment of the active promoter marks (H3K9ac, H3K14ac, H3K4me3 and H3K27ac) at or around TSSs correlate with the increase in gene expression levels. Interestingly, H3K9ac is more spread than the other analyzed active histone marks around the TSSs (Figure2). While Pol II is enriched at or slightly downstream of the TSSs, on these sites the nucleosomes (H3) are depleted (Figure2). This genome-wide observation with various active histone marks is consistent with the notion that H3K9ac and H3K4me3 near the TSSs destabilize interaction between histones and DNA leading to nucleosome eviction [25,26]. Taken together, these results suggest that level of active histone marks (H3K4me3, H3K9ac, H3K14ac and H3K27ac) over the active promoter chromatin state correlates with the magnitude of gene expression.

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