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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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Dynamics of histone occupancy across the P. falciparum IDC.(A) mRNA transcriptome and dynamic occupancy profiles of 13 histone marks across the IDC. The phaseograms depict the cascades of the dynamic occupancy profiles (P<0.05 and fold change ≥1.5 across the IDC, see Figure 1B) for the 13 histone marks. The yellow/blue color scale represents lowess smoothed profiles calculated from centered curves of relative occupancy ratios measured by ChIP/input (log2) for the 6 time points (TP1-6 representing 0 to 48 hpi). The mRNA transcriptome presented on the left was assembled similarly. The gene/probe order in each phaseogram was determined independently using Fast Fourier transformation (see Materials and Methods). (B) Distribution of the peak occupancy of the 13 histone marks along the IDC. The bar chart shows the maximum occupancy of histone marks at 3 life cycle stages for the dynamic profiles included in the phaseograms (panel A). The percentage represented (by bar size) as well as the probe number (number within the bar) depicts the distribution of the corresponding occupancy profiles that peak at TP1 or TP2 (0–16 hpi), TP3 or TP4 (17–32 hpi) and TP5 or TP6 (33–48 hpi). In our culturing set up, these time points correspond to the three main IDC developmental stages, ring, trophozoite and schizont, respectively.
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ppat-1003170-g002: Dynamics of histone occupancy across the P. falciparum IDC.(A) mRNA transcriptome and dynamic occupancy profiles of 13 histone marks across the IDC. The phaseograms depict the cascades of the dynamic occupancy profiles (P<0.05 and fold change ≥1.5 across the IDC, see Figure 1B) for the 13 histone marks. The yellow/blue color scale represents lowess smoothed profiles calculated from centered curves of relative occupancy ratios measured by ChIP/input (log2) for the 6 time points (TP1-6 representing 0 to 48 hpi). The mRNA transcriptome presented on the left was assembled similarly. The gene/probe order in each phaseogram was determined independently using Fast Fourier transformation (see Materials and Methods). (B) Distribution of the peak occupancy of the 13 histone marks along the IDC. The bar chart shows the maximum occupancy of histone marks at 3 life cycle stages for the dynamic profiles included in the phaseograms (panel A). The percentage represented (by bar size) as well as the probe number (number within the bar) depicts the distribution of the corresponding occupancy profiles that peak at TP1 or TP2 (0–16 hpi), TP3 or TP4 (17–32 hpi) and TP5 or TP6 (33–48 hpi). In our culturing set up, these time points correspond to the three main IDC developmental stages, ring, trophozoite and schizont, respectively.

Mentions: Similar to mRNA, the occupancy patterns of histone modifications exhibited single peak profiles with each locus being marked once at a specific time during the IDC (Figure 2A). Investigating the time of peak occupancy, we observed no general trends, but instead each histone mark exhibited a distinct pattern (Figure 2B). In particular, more than 50% of genetic loci are associated with the dynamic occupancy of H4K20me1, H4K20me3 and H3K14ac which reach maximum levels between 0 and 16 hpi, whereas 40% of loci associated with the dynamic occupancy of H3K4me3 and H4K5ac peaked between 17 and 32 hpi. In contrast, H4K8ac, H3K9ac and H4R3me2 showed maximum occupancy (more than 40%) at the late schizont stage. Other histone marks were evenly distributed amongst the three stages. This global variation in the occupancy of histone marks again suggests their distinct role in chromatin remodeling with multiple events during the IDC affecting their overall distribution across the IDC.


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)

Dynamics of histone occupancy across the P. falciparum IDC.(A) mRNA transcriptome and dynamic occupancy profiles of 13 histone marks across the IDC. The phaseograms depict the cascades of the dynamic occupancy profiles (P<0.05 and fold change ≥1.5 across the IDC, see Figure 1B) for the 13 histone marks. The yellow/blue color scale represents lowess smoothed profiles calculated from centered curves of relative occupancy ratios measured by ChIP/input (log2) for the 6 time points (TP1-6 representing 0 to 48 hpi). The mRNA transcriptome presented on the left was assembled similarly. The gene/probe order in each phaseogram was determined independently using Fast Fourier transformation (see Materials and Methods). (B) Distribution of the peak occupancy of the 13 histone marks along the IDC. The bar chart shows the maximum occupancy of histone marks at 3 life cycle stages for the dynamic profiles included in the phaseograms (panel A). The percentage represented (by bar size) as well as the probe number (number within the bar) depicts the distribution of the corresponding occupancy profiles that peak at TP1 or TP2 (0–16 hpi), TP3 or TP4 (17–32 hpi) and TP5 or TP6 (33–48 hpi). In our culturing set up, these time points correspond to the three main IDC developmental stages, ring, trophozoite and schizont, respectively.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585154&req=5

ppat-1003170-g002: Dynamics of histone occupancy across the P. falciparum IDC.(A) mRNA transcriptome and dynamic occupancy profiles of 13 histone marks across the IDC. The phaseograms depict the cascades of the dynamic occupancy profiles (P<0.05 and fold change ≥1.5 across the IDC, see Figure 1B) for the 13 histone marks. The yellow/blue color scale represents lowess smoothed profiles calculated from centered curves of relative occupancy ratios measured by ChIP/input (log2) for the 6 time points (TP1-6 representing 0 to 48 hpi). The mRNA transcriptome presented on the left was assembled similarly. The gene/probe order in each phaseogram was determined independently using Fast Fourier transformation (see Materials and Methods). (B) Distribution of the peak occupancy of the 13 histone marks along the IDC. The bar chart shows the maximum occupancy of histone marks at 3 life cycle stages for the dynamic profiles included in the phaseograms (panel A). The percentage represented (by bar size) as well as the probe number (number within the bar) depicts the distribution of the corresponding occupancy profiles that peak at TP1 or TP2 (0–16 hpi), TP3 or TP4 (17–32 hpi) and TP5 or TP6 (33–48 hpi). In our culturing set up, these time points correspond to the three main IDC developmental stages, ring, trophozoite and schizont, respectively.
Mentions: Similar to mRNA, the occupancy patterns of histone modifications exhibited single peak profiles with each locus being marked once at a specific time during the IDC (Figure 2A). Investigating the time of peak occupancy, we observed no general trends, but instead each histone mark exhibited a distinct pattern (Figure 2B). In particular, more than 50% of genetic loci are associated with the dynamic occupancy of H4K20me1, H4K20me3 and H3K14ac which reach maximum levels between 0 and 16 hpi, whereas 40% of loci associated with the dynamic occupancy of H3K4me3 and H4K5ac peaked between 17 and 32 hpi. In contrast, H4K8ac, H3K9ac and H4R3me2 showed maximum occupancy (more than 40%) at the late schizont stage. Other histone marks were evenly distributed amongst the three stages. This global variation in the occupancy of histone marks again suggests their distinct role in chromatin remodeling with multiple events during the IDC affecting their overall distribution across the IDC.

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