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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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H3K9ac and H3K14ac mark active enhancers along with H3K27ac. (A) Heatmap of the signal density using k-means clustering observed on 25036 putative enhancers (-/+ 5 kb) from mES cells for H3K4me1 (mark of putative enhancers), H3K27ac, H3K9ac and H3K14ac. On the basis of presence or absence of H3K27ac enhancers are categorized as active or poised/inactive. UCSC genome browser track of representative examples of (B) active enhancer and (C) poised/inactive enhancer. Active enhancers have significant enrichment of H3K9ac and H3K14ac as compared to poised/inactive enhancers as was observed for H3K27ac.
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Figure 4: H3K9ac and H3K14ac mark active enhancers along with H3K27ac. (A) Heatmap of the signal density using k-means clustering observed on 25036 putative enhancers (-/+ 5 kb) from mES cells for H3K4me1 (mark of putative enhancers), H3K27ac, H3K9ac and H3K14ac. On the basis of presence or absence of H3K27ac enhancers are categorized as active or poised/inactive. UCSC genome browser track of representative examples of (B) active enhancer and (C) poised/inactive enhancer. Active enhancers have significant enrichment of H3K9ac and H3K14ac as compared to poised/inactive enhancers as was observed for H3K27ac.

Mentions: Transcription from enhancers resulting in enhancer RNAs (eRNAs) play important regulatory role in maintenance of gene expression programs [30-32]. Enhancers are key cis-regulatory elements that can affect gene expression independent of their orientation or distance in a cell type specific manner [9]. Enhancers are marked by the presence of H3K4me1, DNase I hypersensitivity and histone acetyl transferases such as p300 [4,9] or the GCN5/PCAF-containing ATAC complex [10]. The important proportion of H3K9 and H3K14 acetylation sites in distal intergenic regions (Figure1A) motivated us to further analyze these sites for the presence of various histone modifications, Pol II and p300 that are indicative of enhancers. Identification of H3K9ac and H3K14ac peaks in intergenic regions is described in Materials and Methods. During this analysis we found a strong correlation between H3K9ac or H3K14ac intergenic sites with either, H3K4me1, H3K27ac, the presence of Pol II and p300 suggesting that H3K9ac and H3K14ac mark also enhancers ( Additional file 6: Figure S5). To confirm the presence of H3K9ac and H3K14ac over enhancers, we took 25036 putative enhancers reported in mES cells [11] and subjected them to k-means clustering using seqMiner [33]. Further, H3K27ac was used to distinguish active and inactive/poised enhancers. Our analyses show that active enhancers are marked by the strong presence of H3K9ac and H3K14ac along with H3K27ac and H3K4me1 (Figure4A and 4B) and those inactive/poised enhancers are marked by the presence of H3K4me1 together with relatively weak levels of H3K14ac (Figure4A and 4C). Thus, our study suggests that H3K9ac and H3K14ac mark enhancers and can further discriminate active enhancers from poised/inactive enhancers.


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)

H3K9ac and H3K14ac mark active enhancers along with H3K27ac. (A) Heatmap of the signal density using k-means clustering observed on 25036 putative enhancers (-/+ 5 kb) from mES cells for H3K4me1 (mark of putative enhancers), H3K27ac, H3K9ac and H3K14ac. On the basis of presence or absence of H3K27ac enhancers are categorized as active or poised/inactive. UCSC genome browser track of representative examples of (B) active enhancer and (C) poised/inactive enhancer. Active enhancers have significant enrichment of H3K9ac and H3K14ac as compared to poised/inactive enhancers as was observed for H3K27ac.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3473242&req=5

Figure 4: H3K9ac and H3K14ac mark active enhancers along with H3K27ac. (A) Heatmap of the signal density using k-means clustering observed on 25036 putative enhancers (-/+ 5 kb) from mES cells for H3K4me1 (mark of putative enhancers), H3K27ac, H3K9ac and H3K14ac. On the basis of presence or absence of H3K27ac enhancers are categorized as active or poised/inactive. UCSC genome browser track of representative examples of (B) active enhancer and (C) poised/inactive enhancer. Active enhancers have significant enrichment of H3K9ac and H3K14ac as compared to poised/inactive enhancers as was observed for H3K27ac.
Mentions: Transcription from enhancers resulting in enhancer RNAs (eRNAs) play important regulatory role in maintenance of gene expression programs [30-32]. Enhancers are key cis-regulatory elements that can affect gene expression independent of their orientation or distance in a cell type specific manner [9]. Enhancers are marked by the presence of H3K4me1, DNase I hypersensitivity and histone acetyl transferases such as p300 [4,9] or the GCN5/PCAF-containing ATAC complex [10]. The important proportion of H3K9 and H3K14 acetylation sites in distal intergenic regions (Figure1A) motivated us to further analyze these sites for the presence of various histone modifications, Pol II and p300 that are indicative of enhancers. Identification of H3K9ac and H3K14ac peaks in intergenic regions is described in Materials and Methods. During this analysis we found a strong correlation between H3K9ac or H3K14ac intergenic sites with either, H3K4me1, H3K27ac, the presence of Pol II and p300 suggesting that H3K9ac and H3K14ac mark also enhancers ( Additional file 6: Figure S5). To confirm the presence of H3K9ac and H3K14ac over enhancers, we took 25036 putative enhancers reported in mES cells [11] and subjected them to k-means clustering using seqMiner [33]. Further, H3K27ac was used to distinguish active and inactive/poised enhancers. Our analyses show that active enhancers are marked by the strong presence of H3K9ac and H3K14ac along with H3K27ac and H3K4me1 (Figure4A and 4B) and those inactive/poised enhancers are marked by the presence of H3K4me1 together with relatively weak levels of H3K14ac (Figure4A and 4C). Thus, our study suggests that H3K9ac and H3K14ac mark enhancers and can further discriminate active enhancers from poised/inactive enhancers.

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
Related in: MedlinePlus