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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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Selective increase in H3K14ac over inactive genes in presence of sodium butyrate. (A, B) Rapid increase in the H3K9 and H3K14 acetylation over active promoters (Hspd1 and B230219D22Rik) caused by HDAC inhibitor. The upper panels show the UCSC genome browser tracks for the genes analysed. (C, D) Selective increase in H3K14ac over the inactive promoters (4930486L24Rik and Dsc1) as compared to H3K9ac following the treatment with HDAC inhibitor. The upper panels show the UCSC genome browser track for the genes analysed. The presence of H3K9ac and H3K14ac over these loci at the indicated time points after the sodium butyrate treatment was measured by ChIP-qPCR. ChIP signals for H3K9ac and H3K14ac were normalized to total H3. Positions of the primers used for ChIP-qPCR is shown in the UCSC genome browser track and primer sequences are provided in Additional file 4: Table S1. Error bars represent the standard deviation for three technical replicates.
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Figure 7: Selective increase in H3K14ac over inactive genes in presence of sodium butyrate. (A, B) Rapid increase in the H3K9 and H3K14 acetylation over active promoters (Hspd1 and B230219D22Rik) caused by HDAC inhibitor. The upper panels show the UCSC genome browser tracks for the genes analysed. (C, D) Selective increase in H3K14ac over the inactive promoters (4930486L24Rik and Dsc1) as compared to H3K9ac following the treatment with HDAC inhibitor. The upper panels show the UCSC genome browser track for the genes analysed. The presence of H3K9ac and H3K14ac over these loci at the indicated time points after the sodium butyrate treatment was measured by ChIP-qPCR. ChIP signals for H3K9ac and H3K14ac were normalized to total H3. Positions of the primers used for ChIP-qPCR is shown in the UCSC genome browser track and primer sequences are provided in Additional file 4: Table S1. Error bars represent the standard deviation for three technical replicates.

Mentions: To understand the functionality of H3K14ac over inactive promoters, we examined the level of this histone mark over active and inactive genes in presence of sodium butyrate, a HDAC inhibitor, and compared it to H3K9ac. In agreement with our above observations, we found that active genes exhibited a remarkable increase in H3K9ac and H3K14ac in presence of sodium butyrate (Figure7A and 7B). However, examination of H3K9ac and H3K14ac level at inactive genes in presence of sodium butyrate revealed a slow and selective increase in H3K14ac, while at these sites H3K9ac did not change (Figure7C and 7D). The selective increase in H3K14ac at inactive genes in presence of sodium butyrate suggests that inactive genes are subjected to constant H3K14 acetylation and deacetylation. This dynamic H3K14ac at inactive genes may poise them for future activation. To test this hypothesis, we selected 500 inactive genes having higher H3K14ac as compared to H3K9ac (Figure8A) and subjected them to gene ontology (Figure8B). Our analysis suggests that inactive genes, which are having significant H3K14ac over H3K9ac belong to various pathways that are induced by various stimuli such as sensory perception, olfaction and chemosensory perception. Other pathways include receptor activities, which are induced upon ligand binding to activate the signal transduction and ultimately cellular responses (Figure8B). Thus, our data indicate that H3K14ac is selectively present over a subset of non-expressed genes and HDACs frequently remove this mark to keep the genes inactive. The coordinated action of HATs and HDACs may poise these genes for stimuli dependent activation.


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)

Selective increase in H3K14ac over inactive genes in presence of sodium butyrate. (A, B) Rapid increase in the H3K9 and H3K14 acetylation over active promoters (Hspd1 and B230219D22Rik) caused by HDAC inhibitor. The upper panels show the UCSC genome browser tracks for the genes analysed. (C, D) Selective increase in H3K14ac over the inactive promoters (4930486L24Rik and Dsc1) as compared to H3K9ac following the treatment with HDAC inhibitor. The upper panels show the UCSC genome browser track for the genes analysed. The presence of H3K9ac and H3K14ac over these loci at the indicated time points after the sodium butyrate treatment was measured by ChIP-qPCR. ChIP signals for H3K9ac and H3K14ac were normalized to total H3. Positions of the primers used for ChIP-qPCR is shown in the UCSC genome browser track and primer sequences are provided in Additional file 4: Table S1. Error bars represent the standard deviation for three technical replicates.
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Related In: Results  -  Collection

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Figure 7: Selective increase in H3K14ac over inactive genes in presence of sodium butyrate. (A, B) Rapid increase in the H3K9 and H3K14 acetylation over active promoters (Hspd1 and B230219D22Rik) caused by HDAC inhibitor. The upper panels show the UCSC genome browser tracks for the genes analysed. (C, D) Selective increase in H3K14ac over the inactive promoters (4930486L24Rik and Dsc1) as compared to H3K9ac following the treatment with HDAC inhibitor. The upper panels show the UCSC genome browser track for the genes analysed. The presence of H3K9ac and H3K14ac over these loci at the indicated time points after the sodium butyrate treatment was measured by ChIP-qPCR. ChIP signals for H3K9ac and H3K14ac were normalized to total H3. Positions of the primers used for ChIP-qPCR is shown in the UCSC genome browser track and primer sequences are provided in Additional file 4: Table S1. Error bars represent the standard deviation for three technical replicates.
Mentions: To understand the functionality of H3K14ac over inactive promoters, we examined the level of this histone mark over active and inactive genes in presence of sodium butyrate, a HDAC inhibitor, and compared it to H3K9ac. In agreement with our above observations, we found that active genes exhibited a remarkable increase in H3K9ac and H3K14ac in presence of sodium butyrate (Figure7A and 7B). However, examination of H3K9ac and H3K14ac level at inactive genes in presence of sodium butyrate revealed a slow and selective increase in H3K14ac, while at these sites H3K9ac did not change (Figure7C and 7D). The selective increase in H3K14ac at inactive genes in presence of sodium butyrate suggests that inactive genes are subjected to constant H3K14 acetylation and deacetylation. This dynamic H3K14ac at inactive genes may poise them for future activation. To test this hypothesis, we selected 500 inactive genes having higher H3K14ac as compared to H3K9ac (Figure8A) and subjected them to gene ontology (Figure8B). Our analysis suggests that inactive genes, which are having significant H3K14ac over H3K9ac belong to various pathways that are induced by various stimuli such as sensory perception, olfaction and chemosensory perception. Other pathways include receptor activities, which are induced upon ligand binding to activate the signal transduction and ultimately cellular responses (Figure8B). Thus, our data indicate that H3K14ac is selectively present over a subset of non-expressed genes and HDACs frequently remove this mark to keep the genes inactive. The coordinated action of HATs and HDACs may poise these genes for stimuli dependent activation.

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