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Dynamic epigenetic regulation of gene expression during the life cycle of malaria parasite Plasmodium falciparum.

Gupta AP, Chin WH, Zhu L, Mok S, Luah YH, Lim EH, Bozdech Z - PLoS Pathog. (2013)

Bottom Line: While some modifications were found to be associated with the vast majority of the genome and their occupancy was constant, others showed more specific and highly dynamic distribution.In addition, we showed the presence of multivalent domains on the genome carrying more than one histone mark, highlighting the importance of combinatorial effects on transcription.Overall, our work portrays a substantial association between chromosomal locations of various epigenetic markers, transcriptional activity and global stage-specific transitions in the epigenome.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.

ABSTRACT
Epigenetic mechanisms are emerging as one of the major factors of the dynamics of gene expression in the human malaria parasite, Plasmodium falciparum. To elucidate the role of chromatin remodeling in transcriptional regulation associated with the progression of the P. falciparum intraerythrocytic development cycle (IDC), we mapped the temporal pattern of chromosomal association with histone H3 and H4 modifications using ChIP-on-chip. Here, we have generated a broad integrative epigenomic map of twelve histone modifications during the P. falciparum IDC including H4K5ac, H4K8ac, H4K12ac, H4K16ac, H3K9ac, H3K14ac, H3K56ac, H4K20me1, H4K20me3, H3K4me3, H3K79me3 and H4R3me2. While some modifications were found to be associated with the vast majority of the genome and their occupancy was constant, others showed more specific and highly dynamic distribution. Importantly, eight modifications displaying tight correlations with transcript levels showed differential affinity to distinct genomic regions with H4K8ac occupying predominantly promoter regions while others occurred at the 5' ends of coding sequences. The promoter occupancy of H4K8ac remained unchanged when ectopically inserted at a different locus, indicating the presence of specific DNA elements that recruit histone modifying enzymes regardless of their broad chromatin environment. In addition, we showed the presence of multivalent domains on the genome carrying more than one histone mark, highlighting the importance of combinatorial effects on transcription. Overall, our work portrays a substantial association between chromosomal locations of various epigenetic markers, transcriptional activity and global stage-specific transitions in the epigenome.

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Gene positioning and biological significance of the transcription-linked histone marks.The plots on the left represent the frequency (percentage) of transcription-linked histone marks that are characterized by their dynamic occupancy profiles with positive (r≥0.4) or negative (r≤−0.4) correlation with expression. The frequency of these transcription-linked profiles is plotted along an average gene corresponding to the genetic locus/probe positioning within the gene. In particular, the data was arranged into 500 bp bins ranging from 1500 bp upstream of the ATG start codon (“Promoter”) to +3000 bp into the gene (“Coding body”). The frequency (y-axis) is expressed as the percentage of transcription-linked profiles versus the total number of occupancy profiles (both dynamic and constitutive) for either positive (dark green, above the x-axis) or negative (light green, below the x-axis). The vertical dotted line marks the position of the ATG start codon. Functional enrichment analyses identified over-represented pathways (P<0.05) as compared to their respective frequency in the genome for genes associated with each transcription-linked modification (right).
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ppat-1003170-g004: Gene positioning and biological significance of the transcription-linked histone marks.The plots on the left represent the frequency (percentage) of transcription-linked histone marks that are characterized by their dynamic occupancy profiles with positive (r≥0.4) or negative (r≤−0.4) correlation with expression. The frequency of these transcription-linked profiles is plotted along an average gene corresponding to the genetic locus/probe positioning within the gene. In particular, the data was arranged into 500 bp bins ranging from 1500 bp upstream of the ATG start codon (“Promoter”) to +3000 bp into the gene (“Coding body”). The frequency (y-axis) is expressed as the percentage of transcription-linked profiles versus the total number of occupancy profiles (both dynamic and constitutive) for either positive (dark green, above the x-axis) or negative (light green, below the x-axis). The vertical dotted line marks the position of the ATG start codon. Functional enrichment analyses identified over-represented pathways (P<0.05) as compared to their respective frequency in the genome for genes associated with each transcription-linked modification (right).

Mentions: Next, we were interested in the biological significance of the transcription-linked histone modifications. We analyzed the distribution of mRNA correlating histone-marked loci with respect to their position in the gene and subsequently investigated the functional involvement of these genes (Figure 4). Interestingly only one dynamic, transcription-linked histone mark (H4K8ac) showed a strong presence for the IGRs and/or 5′ untranslated regions (5′UTR). This is in good agreement with its overall distribution in the genome (see Figure 1D). All other modifications associated with transcription, including H3K9ac, H3K4me3, H3K56ac, H3K4me3, H4K16ac and H4ac4, appear to accumulate mainly at the 5′ ends of the ORFs. Transcription-linked occupancy of H4K20me1 and H3K14ac showed no positional preference. We did not observe any positional bias for probes negatively correlated with expression (r≤−0.4).


Dynamic epigenetic regulation of gene expression during the life cycle of malaria parasite Plasmodium falciparum.

Gupta AP, Chin WH, Zhu L, Mok S, Luah YH, Lim EH, Bozdech Z - PLoS Pathog. (2013)

Gene positioning and biological significance of the transcription-linked histone marks.The plots on the left represent the frequency (percentage) of transcription-linked histone marks that are characterized by their dynamic occupancy profiles with positive (r≥0.4) or negative (r≤−0.4) correlation with expression. The frequency of these transcription-linked profiles is plotted along an average gene corresponding to the genetic locus/probe positioning within the gene. In particular, the data was arranged into 500 bp bins ranging from 1500 bp upstream of the ATG start codon (“Promoter”) to +3000 bp into the gene (“Coding body”). The frequency (y-axis) is expressed as the percentage of transcription-linked profiles versus the total number of occupancy profiles (both dynamic and constitutive) for either positive (dark green, above the x-axis) or negative (light green, below the x-axis). The vertical dotted line marks the position of the ATG start codon. Functional enrichment analyses identified over-represented pathways (P<0.05) as compared to their respective frequency in the genome for genes associated with each transcription-linked modification (right).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585154&req=5

ppat-1003170-g004: Gene positioning and biological significance of the transcription-linked histone marks.The plots on the left represent the frequency (percentage) of transcription-linked histone marks that are characterized by their dynamic occupancy profiles with positive (r≥0.4) or negative (r≤−0.4) correlation with expression. The frequency of these transcription-linked profiles is plotted along an average gene corresponding to the genetic locus/probe positioning within the gene. In particular, the data was arranged into 500 bp bins ranging from 1500 bp upstream of the ATG start codon (“Promoter”) to +3000 bp into the gene (“Coding body”). The frequency (y-axis) is expressed as the percentage of transcription-linked profiles versus the total number of occupancy profiles (both dynamic and constitutive) for either positive (dark green, above the x-axis) or negative (light green, below the x-axis). The vertical dotted line marks the position of the ATG start codon. Functional enrichment analyses identified over-represented pathways (P<0.05) as compared to their respective frequency in the genome for genes associated with each transcription-linked modification (right).
Mentions: Next, we were interested in the biological significance of the transcription-linked histone modifications. We analyzed the distribution of mRNA correlating histone-marked loci with respect to their position in the gene and subsequently investigated the functional involvement of these genes (Figure 4). Interestingly only one dynamic, transcription-linked histone mark (H4K8ac) showed a strong presence for the IGRs and/or 5′ untranslated regions (5′UTR). This is in good agreement with its overall distribution in the genome (see Figure 1D). All other modifications associated with transcription, including H3K9ac, H3K4me3, H3K56ac, H3K4me3, H4K16ac and H4ac4, appear to accumulate mainly at the 5′ ends of the ORFs. Transcription-linked occupancy of H4K20me1 and H3K14ac showed no positional preference. We did not observe any positional bias for probes negatively correlated with expression (r≤−0.4).

Bottom Line: While some modifications were found to be associated with the vast majority of the genome and their occupancy was constant, others showed more specific and highly dynamic distribution.In addition, we showed the presence of multivalent domains on the genome carrying more than one histone mark, highlighting the importance of combinatorial effects on transcription.Overall, our work portrays a substantial association between chromosomal locations of various epigenetic markers, transcriptional activity and global stage-specific transitions in the epigenome.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.

ABSTRACT
Epigenetic mechanisms are emerging as one of the major factors of the dynamics of gene expression in the human malaria parasite, Plasmodium falciparum. To elucidate the role of chromatin remodeling in transcriptional regulation associated with the progression of the P. falciparum intraerythrocytic development cycle (IDC), we mapped the temporal pattern of chromosomal association with histone H3 and H4 modifications using ChIP-on-chip. Here, we have generated a broad integrative epigenomic map of twelve histone modifications during the P. falciparum IDC including H4K5ac, H4K8ac, H4K12ac, H4K16ac, H3K9ac, H3K14ac, H3K56ac, H4K20me1, H4K20me3, H3K4me3, H3K79me3 and H4R3me2. While some modifications were found to be associated with the vast majority of the genome and their occupancy was constant, others showed more specific and highly dynamic distribution. Importantly, eight modifications displaying tight correlations with transcript levels showed differential affinity to distinct genomic regions with H4K8ac occupying predominantly promoter regions while others occurred at the 5' ends of coding sequences. The promoter occupancy of H4K8ac remained unchanged when ectopically inserted at a different locus, indicating the presence of specific DNA elements that recruit histone modifying enzymes regardless of their broad chromatin environment. In addition, we showed the presence of multivalent domains on the genome carrying more than one histone mark, highlighting the importance of combinatorial effects on transcription. Overall, our work portrays a substantial association between chromosomal locations of various epigenetic markers, transcriptional activity and global stage-specific transitions in the epigenome.

Show MeSH
Related in: MedlinePlus