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5' flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites.

Lopez-Rubio JJ, Gontijo AM, Nunes MC, Issar N, Hernandez Rivas R, Scherf A - Mol. Microbiol. (2007)

Bottom Line: Tri- and dimethylation of histone H3 lysine 4 peak in the 5' upstream region of transcribed var and during the poised state (non-transcribed phase of var genes during the 48 h asexual life cycle), 'bookmarking' this member for re-activation at the onset of the next cycle.Histone H3 lysine 9 trimethylation acts as an antagonist to lysine 4 methylation to establish stably silent var gene states along the 5' flanking and coding region.Furthermore, we show that competition exists between H3K9 methylation and H3K9 acetylation in the 5' flanking region and that these marks contribute epigenetically to repressing or activating var gene expression.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur-CNRS, 25 rue du Dr Roux, 75724 Paris, France.

ABSTRACT
In the human malaria parasite Plasmodium falciparum antigenic variation facilitates long-term chronic infection of the host. This is achieved by sequential expression of a single member of the 60-member var family. Here we show that the 5' flanking region nucleates epigenetic events strongly linked to the maintenance of mono-allelic var gene expression pattern during parasite proliferation. Tri- and dimethylation of histone H3 lysine 4 peak in the 5' upstream region of transcribed var and during the poised state (non-transcribed phase of var genes during the 48 h asexual life cycle), 'bookmarking' this member for re-activation at the onset of the next cycle. Histone H3 lysine 9 trimethylation acts as an antagonist to lysine 4 methylation to establish stably silent var gene states along the 5' flanking and coding region. Furthermore, we show that competition exists between H3K9 methylation and H3K9 acetylation in the 5' flanking region and that these marks contribute epigenetically to repressing or activating var gene expression. Our work points to a pivotal role of the histone methyl mark writing and reading machinery in the phenotypic inheritance of virulence traits in the malaria parasite.

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Acetylated and methylated H3K9 levels at var2csa.A. Distribution of H3K9ac (white bars) and H3K9me3 (black bars) along the active var2csa gene in FCR3 CSA ring stage parasites.B. Distribution of H3K9ac (white bars) and H3K9me3 (black bars) along the silent var2csa gene in FCR3 CD36 ring stage parasites. The data are plotted as for Fig. 3. Note that the H3K9ac antibody gives stronger signals and that the y-axes are different for the two antibodies.
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fig06: Acetylated and methylated H3K9 levels at var2csa.A. Distribution of H3K9ac (white bars) and H3K9me3 (black bars) along the active var2csa gene in FCR3 CSA ring stage parasites.B. Distribution of H3K9ac (white bars) and H3K9me3 (black bars) along the silent var2csa gene in FCR3 CD36 ring stage parasites. The data are plotted as for Fig. 3. Note that the H3K9ac antibody gives stronger signals and that the y-axes are different for the two antibodies.

Mentions: As the active var2csa gene is deprived of H3K9me3 at the 5′ upstream region (Fig. 3) and H3K9ac can be a mark of active housekeeping genes in P. falciparum (Cui et al., 2007), we investigated weather the methylation mark of H3K9 would be replaced by acetylation in the active var gene. To test this hypothesis, we analysed H3K9ac across the var2csa gene and compared this with H3K9me3 in its active and silent state (Fig. 6). H3K9ac was specifically enriched at the 5′ flanking regions of the active var gene, showing an opposite distribution of that observed for H3K9me3. Thus, both histone H3 acetylation and methylation marks define active var states yet in distinct N-terminal lysine positions.


5' flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites.

Lopez-Rubio JJ, Gontijo AM, Nunes MC, Issar N, Hernandez Rivas R, Scherf A - Mol. Microbiol. (2007)

Acetylated and methylated H3K9 levels at var2csa.A. Distribution of H3K9ac (white bars) and H3K9me3 (black bars) along the active var2csa gene in FCR3 CSA ring stage parasites.B. Distribution of H3K9ac (white bars) and H3K9me3 (black bars) along the silent var2csa gene in FCR3 CD36 ring stage parasites. The data are plotted as for Fig. 3. Note that the H3K9ac antibody gives stronger signals and that the y-axes are different for the two antibodies.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2228885&req=5

fig06: Acetylated and methylated H3K9 levels at var2csa.A. Distribution of H3K9ac (white bars) and H3K9me3 (black bars) along the active var2csa gene in FCR3 CSA ring stage parasites.B. Distribution of H3K9ac (white bars) and H3K9me3 (black bars) along the silent var2csa gene in FCR3 CD36 ring stage parasites. The data are plotted as for Fig. 3. Note that the H3K9ac antibody gives stronger signals and that the y-axes are different for the two antibodies.
Mentions: As the active var2csa gene is deprived of H3K9me3 at the 5′ upstream region (Fig. 3) and H3K9ac can be a mark of active housekeeping genes in P. falciparum (Cui et al., 2007), we investigated weather the methylation mark of H3K9 would be replaced by acetylation in the active var gene. To test this hypothesis, we analysed H3K9ac across the var2csa gene and compared this with H3K9me3 in its active and silent state (Fig. 6). H3K9ac was specifically enriched at the 5′ flanking regions of the active var gene, showing an opposite distribution of that observed for H3K9me3. Thus, both histone H3 acetylation and methylation marks define active var states yet in distinct N-terminal lysine positions.

Bottom Line: Tri- and dimethylation of histone H3 lysine 4 peak in the 5' upstream region of transcribed var and during the poised state (non-transcribed phase of var genes during the 48 h asexual life cycle), 'bookmarking' this member for re-activation at the onset of the next cycle.Histone H3 lysine 9 trimethylation acts as an antagonist to lysine 4 methylation to establish stably silent var gene states along the 5' flanking and coding region.Furthermore, we show that competition exists between H3K9 methylation and H3K9 acetylation in the 5' flanking region and that these marks contribute epigenetically to repressing or activating var gene expression.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur-CNRS, 25 rue du Dr Roux, 75724 Paris, France.

ABSTRACT
In the human malaria parasite Plasmodium falciparum antigenic variation facilitates long-term chronic infection of the host. This is achieved by sequential expression of a single member of the 60-member var family. Here we show that the 5' flanking region nucleates epigenetic events strongly linked to the maintenance of mono-allelic var gene expression pattern during parasite proliferation. Tri- and dimethylation of histone H3 lysine 4 peak in the 5' upstream region of transcribed var and during the poised state (non-transcribed phase of var genes during the 48 h asexual life cycle), 'bookmarking' this member for re-activation at the onset of the next cycle. Histone H3 lysine 9 trimethylation acts as an antagonist to lysine 4 methylation to establish stably silent var gene states along the 5' flanking and coding region. Furthermore, we show that competition exists between H3K9 methylation and H3K9 acetylation in the 5' flanking region and that these marks contribute epigenetically to repressing or activating var gene expression. Our work points to a pivotal role of the histone methyl mark writing and reading machinery in the phenotypic inheritance of virulence traits in the malaria parasite.

Show MeSH
Related in: MedlinePlus