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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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Association of histone mark occupancy with transcription.(A) Correlation of H4K8ac occupancy with transcription. The dynamic occupancy profiles for H4K8ac (leftmost panel) was correlated to the corresponding mRNA profiles using Pearson Correlation Coefficient (PCC, also r). The PCC was calculated between each dynamic H4K8ac occupancy profile and mRNA abundance profile of the corresponding gene. The PCC distribution was plotted along bins ranging from −1 to +1 (x-axis) as the number of probes in each bin (bar graph in the middle). A total of 3,356 probes showed r (PCC)≥0.4 which represents a good correlation in the IDC timing (rightmost panels). In addition 2090 probes showed no correlation (r between 0.4 and −0.4) and 1632 probes showed a negative correlation (r≤−0.4) with expression. Out of 7,260 loci linked with the dynamic H4K8ac occupancy profiles, we did not obtain expression data for 182 probes. The scale bar refers to log2 ratios of mean-centered profiles across the IDC. (B) Correlations of the 13 histone-mark-occupancy profiles with transcription. Similar to H4K8ac (panel A), the distribution of PCC (r) correlations between the dynamic occupancy and steady state mRNA profiles were calculated for all 13 studied histone marks. Similarly, the data were arranged into bins of PCC ranging from −1 to +1 (x-axis) and plotted against the number of probes in each bin for actual distribution (bar graphs) and randomized distribution (line graphs). The statistical significance of the observed distribution (P, tested against the randomized distributions) and the degree of skewness (S, positive values towards positive PCCs) of the PCC distribution is presented at the right bottom of each graph (see Materials and Methods). Eight histone marks exhibit statistically significant correlation with transcript levels (purple graphs) while 5 marks show a neutral relationship with transcript levels (green bars).
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ppat-1003170-g003: Association of histone mark occupancy with transcription.(A) Correlation of H4K8ac occupancy with transcription. The dynamic occupancy profiles for H4K8ac (leftmost panel) was correlated to the corresponding mRNA profiles using Pearson Correlation Coefficient (PCC, also r). The PCC was calculated between each dynamic H4K8ac occupancy profile and mRNA abundance profile of the corresponding gene. The PCC distribution was plotted along bins ranging from −1 to +1 (x-axis) as the number of probes in each bin (bar graph in the middle). A total of 3,356 probes showed r (PCC)≥0.4 which represents a good correlation in the IDC timing (rightmost panels). In addition 2090 probes showed no correlation (r between 0.4 and −0.4) and 1632 probes showed a negative correlation (r≤−0.4) with expression. Out of 7,260 loci linked with the dynamic H4K8ac occupancy profiles, we did not obtain expression data for 182 probes. The scale bar refers to log2 ratios of mean-centered profiles across the IDC. (B) Correlations of the 13 histone-mark-occupancy profiles with transcription. Similar to H4K8ac (panel A), the distribution of PCC (r) correlations between the dynamic occupancy and steady state mRNA profiles were calculated for all 13 studied histone marks. Similarly, the data were arranged into bins of PCC ranging from −1 to +1 (x-axis) and plotted against the number of probes in each bin for actual distribution (bar graphs) and randomized distribution (line graphs). The statistical significance of the observed distribution (P, tested against the randomized distributions) and the degree of skewness (S, positive values towards positive PCCs) of the PCC distribution is presented at the right bottom of each graph (see Materials and Methods). Eight histone marks exhibit statistically significant correlation with transcript levels (purple graphs) while 5 marks show a neutral relationship with transcript levels (green bars).

Mentions: The dynamic character of the histone modifications and its similarity to the mRNA abundance profiles during the IDC suggests their possible role in transcription. To investigate this, we evaluated the correlations between the occupancy profiles of the dynamic histone marks and steady state mRNA levels of the corresponding genes. Here we hypothesize that a synchrony between the histone marks and mRNA substantiates a link between their deposition at a particular gene and transcriptional activity. Hence we calculated Pearson Correlation Coefficients (PCC or r) between mean-centered profiles of the dynamic histone modification occupancy and the corresponding mRNA. For example, 49% (out of 7260) of the H4K8ac dynamic occupancy profiles showed positive correlations (r≥0.4) with transcription while 22.8 and 22.5% showed no or negative correlation, respectively (Figure 3A). The overall skew of the H4K8ac correlation values to the positive side suggests that this histone mark plays a role in transcriptional induction. Using the Kolmogorov-Smirnov test (KS test) against randomized data, we were able to evaluate the significance of the occupancy profile correlations with mRNA for all histone marks (Figure 3B). In addition, we utilized the degree of skewness (S) to identify all histone marks that are positively correlated with transcription. With P<0.0005 and S>0.05, we identified eight histone marks including H4K8ac, H4K16ac, H4ac4, H3K56ac, H3K9ac, H3K14ac, H3K4me3 and H4K20me1 that showed positive correlations with transcription and thus we refer to these as “transcription-linked” histone marks. For these eight histone marks, the percentage of probes that show a positive correlation with expression (r≥0.4) varied from 35 to 48% (Figure S4A). The genes associated with these transcription-linked histone marks show no bias to any particular developmental stage but instead are more or less evenly distributed amongst all stages of the IDC (Figure S4B). Interestingly, the histone marks which followed transcription are also amongst the most dynamic, with at least 25% of the loci changing their occupancy across the IDC (see Figure 1B). There was a statistically significant link between one histone modification (H4K5ac) and transcription that is skewed towards a negative correlation. Although H4K5ac is predominantly a constitutive histone mark, this observation opens the possibility that this otherwise euchromatic mark may play a role in transcriptional repression in a small group of genes. Four histone modifications (H4K20me3, H4R3me2, H4K12ac and H3K79me3) show essentially no association with transcription during the IDC (Figure 3B). One interesting example is H4K20me3 which was shown to be present at both heterochromatic and euchromatic domains of the P. falciparum genome [12]. In the future, it will be interesting to study their potential roles in chromatin structure and remodeling which may be distinct from transcription.


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)

Association of histone mark occupancy with transcription.(A) Correlation of H4K8ac occupancy with transcription. The dynamic occupancy profiles for H4K8ac (leftmost panel) was correlated to the corresponding mRNA profiles using Pearson Correlation Coefficient (PCC, also r). The PCC was calculated between each dynamic H4K8ac occupancy profile and mRNA abundance profile of the corresponding gene. The PCC distribution was plotted along bins ranging from −1 to +1 (x-axis) as the number of probes in each bin (bar graph in the middle). A total of 3,356 probes showed r (PCC)≥0.4 which represents a good correlation in the IDC timing (rightmost panels). In addition 2090 probes showed no correlation (r between 0.4 and −0.4) and 1632 probes showed a negative correlation (r≤−0.4) with expression. Out of 7,260 loci linked with the dynamic H4K8ac occupancy profiles, we did not obtain expression data for 182 probes. The scale bar refers to log2 ratios of mean-centered profiles across the IDC. (B) Correlations of the 13 histone-mark-occupancy profiles with transcription. Similar to H4K8ac (panel A), the distribution of PCC (r) correlations between the dynamic occupancy and steady state mRNA profiles were calculated for all 13 studied histone marks. Similarly, the data were arranged into bins of PCC ranging from −1 to +1 (x-axis) and plotted against the number of probes in each bin for actual distribution (bar graphs) and randomized distribution (line graphs). The statistical significance of the observed distribution (P, tested against the randomized distributions) and the degree of skewness (S, positive values towards positive PCCs) of the PCC distribution is presented at the right bottom of each graph (see Materials and Methods). Eight histone marks exhibit statistically significant correlation with transcript levels (purple graphs) while 5 marks show a neutral relationship with transcript levels (green bars).
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Related In: Results  -  Collection

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

ppat-1003170-g003: Association of histone mark occupancy with transcription.(A) Correlation of H4K8ac occupancy with transcription. The dynamic occupancy profiles for H4K8ac (leftmost panel) was correlated to the corresponding mRNA profiles using Pearson Correlation Coefficient (PCC, also r). The PCC was calculated between each dynamic H4K8ac occupancy profile and mRNA abundance profile of the corresponding gene. The PCC distribution was plotted along bins ranging from −1 to +1 (x-axis) as the number of probes in each bin (bar graph in the middle). A total of 3,356 probes showed r (PCC)≥0.4 which represents a good correlation in the IDC timing (rightmost panels). In addition 2090 probes showed no correlation (r between 0.4 and −0.4) and 1632 probes showed a negative correlation (r≤−0.4) with expression. Out of 7,260 loci linked with the dynamic H4K8ac occupancy profiles, we did not obtain expression data for 182 probes. The scale bar refers to log2 ratios of mean-centered profiles across the IDC. (B) Correlations of the 13 histone-mark-occupancy profiles with transcription. Similar to H4K8ac (panel A), the distribution of PCC (r) correlations between the dynamic occupancy and steady state mRNA profiles were calculated for all 13 studied histone marks. Similarly, the data were arranged into bins of PCC ranging from −1 to +1 (x-axis) and plotted against the number of probes in each bin for actual distribution (bar graphs) and randomized distribution (line graphs). The statistical significance of the observed distribution (P, tested against the randomized distributions) and the degree of skewness (S, positive values towards positive PCCs) of the PCC distribution is presented at the right bottom of each graph (see Materials and Methods). Eight histone marks exhibit statistically significant correlation with transcript levels (purple graphs) while 5 marks show a neutral relationship with transcript levels (green bars).
Mentions: The dynamic character of the histone modifications and its similarity to the mRNA abundance profiles during the IDC suggests their possible role in transcription. To investigate this, we evaluated the correlations between the occupancy profiles of the dynamic histone marks and steady state mRNA levels of the corresponding genes. Here we hypothesize that a synchrony between the histone marks and mRNA substantiates a link between their deposition at a particular gene and transcriptional activity. Hence we calculated Pearson Correlation Coefficients (PCC or r) between mean-centered profiles of the dynamic histone modification occupancy and the corresponding mRNA. For example, 49% (out of 7260) of the H4K8ac dynamic occupancy profiles showed positive correlations (r≥0.4) with transcription while 22.8 and 22.5% showed no or negative correlation, respectively (Figure 3A). The overall skew of the H4K8ac correlation values to the positive side suggests that this histone mark plays a role in transcriptional induction. Using the Kolmogorov-Smirnov test (KS test) against randomized data, we were able to evaluate the significance of the occupancy profile correlations with mRNA for all histone marks (Figure 3B). In addition, we utilized the degree of skewness (S) to identify all histone marks that are positively correlated with transcription. With P<0.0005 and S>0.05, we identified eight histone marks including H4K8ac, H4K16ac, H4ac4, H3K56ac, H3K9ac, H3K14ac, H3K4me3 and H4K20me1 that showed positive correlations with transcription and thus we refer to these as “transcription-linked” histone marks. For these eight histone marks, the percentage of probes that show a positive correlation with expression (r≥0.4) varied from 35 to 48% (Figure S4A). The genes associated with these transcription-linked histone marks show no bias to any particular developmental stage but instead are more or less evenly distributed amongst all stages of the IDC (Figure S4B). Interestingly, the histone marks which followed transcription are also amongst the most dynamic, with at least 25% of the loci changing their occupancy across the IDC (see Figure 1B). There was a statistically significant link between one histone modification (H4K5ac) and transcription that is skewed towards a negative correlation. Although H4K5ac is predominantly a constitutive histone mark, this observation opens the possibility that this otherwise euchromatic mark may play a role in transcriptional repression in a small group of genes. Four histone modifications (H4K20me3, H4R3me2, H4K12ac and H3K79me3) show essentially no association with transcription during the IDC (Figure 3B). One interesting example is H4K20me3 which was shown to be present at both heterochromatic and euchromatic domains of the P. falciparum genome [12]. In the future, it will be interesting to study their potential roles in chromatin structure and remodeling which may be distinct from transcription.

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