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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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Trimethylated H3K4 levels at var2csa.A. Distribution of H3K4 trimethylation along the var2csa gene in CSA (white bars) and CD36 ring parasites (black bars).B. Distribution of H3K4 trimethylation along the var2csa gene in CSA (white bars) and CD36 mature parasites (black bars).C. Levels of trimethylated H3K4 (fold enrichment over the same positions in chromatin from CD36 parasites) along the var2csa gene in CSA parasites on ring stages (white bars) and mature stages (black bars).D. Levels of trimethylated H3K4 (fold enrichment over the chromatin from CD36 parasites) at GBP130 and PfGam genes in CSA parasites on ring stages (white bars) and mature stages (black bars).E. Levels of H3K4 trimethylation at GBP130 and PfGam genes in CSA (white bars) and in CD36 ring parasites (black bars). The data are plotted as for Fig. 3.
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fig04: Trimethylated H3K4 levels at var2csa.A. Distribution of H3K4 trimethylation along the var2csa gene in CSA (white bars) and CD36 ring parasites (black bars).B. Distribution of H3K4 trimethylation along the var2csa gene in CSA (white bars) and CD36 mature parasites (black bars).C. Levels of trimethylated H3K4 (fold enrichment over the same positions in chromatin from CD36 parasites) along the var2csa gene in CSA parasites on ring stages (white bars) and mature stages (black bars).D. Levels of trimethylated H3K4 (fold enrichment over the chromatin from CD36 parasites) at GBP130 and PfGam genes in CSA parasites on ring stages (white bars) and mature stages (black bars).E. Levels of H3K4 trimethylation at GBP130 and PfGam genes in CSA (white bars) and in CD36 ring parasites (black bars). The data are plotted as for Fig. 3.

Mentions: Particular histone methylation marks, such as H3K4 modifications, have been associated with transcriptional activity in other organisms. Trimethylated H3K4 is associated with active genes and dimethyl H3K4 correlates with a ‘permissive’ state of chromatin, in which genes are either active or potentially active (Schneider et al., 2004). We next investigated the role of these marks in var gene transcriptional control. ChIP analyses with antibodies against trimethylated H3K4 show that there is a prominent localized enrichment of trimethyl H3K4 at the 5′ flanking region of the var2csaON (Fig. 4A/C, A–C primers, white bars). There is also an enrichment of dimethylated H3K4 in the 5′ upstream region and early coding region of the var2csaON (Fig. 5A/C, A–E primers, white bars). Our results show that di- and trimethylated H3K4 marks differentiate active var members from stably repressed var gene members. To assess whether high levels of these modifications are a universal feature of active genes in P. falciparum, we analysed a single copy gene (GBP130) that is highly transcribed in asexual blood stage parasites (Figs 4D/E and 5D/E). The GBP130 gene contains significant amounts of di- and trimethylated H3K4. The silent PfGam gene carries only low levels of these marks. Thus, similar marks are associated with the transcription of single copy genes in asexual blood stage parasites. Genome wide analysis of the H3K4 methyl mark using ChIP-on-chip could reveal, at a more global level, actively transcribed genes of P. falciparum blood stage parasites.


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)

Trimethylated H3K4 levels at var2csa.A. Distribution of H3K4 trimethylation along the var2csa gene in CSA (white bars) and CD36 ring parasites (black bars).B. Distribution of H3K4 trimethylation along the var2csa gene in CSA (white bars) and CD36 mature parasites (black bars).C. Levels of trimethylated H3K4 (fold enrichment over the same positions in chromatin from CD36 parasites) along the var2csa gene in CSA parasites on ring stages (white bars) and mature stages (black bars).D. Levels of trimethylated H3K4 (fold enrichment over the chromatin from CD36 parasites) at GBP130 and PfGam genes in CSA parasites on ring stages (white bars) and mature stages (black bars).E. Levels of H3K4 trimethylation at GBP130 and PfGam genes in CSA (white bars) and in CD36 ring parasites (black bars). The data are plotted as for Fig. 3.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2228885&req=5

fig04: Trimethylated H3K4 levels at var2csa.A. Distribution of H3K4 trimethylation along the var2csa gene in CSA (white bars) and CD36 ring parasites (black bars).B. Distribution of H3K4 trimethylation along the var2csa gene in CSA (white bars) and CD36 mature parasites (black bars).C. Levels of trimethylated H3K4 (fold enrichment over the same positions in chromatin from CD36 parasites) along the var2csa gene in CSA parasites on ring stages (white bars) and mature stages (black bars).D. Levels of trimethylated H3K4 (fold enrichment over the chromatin from CD36 parasites) at GBP130 and PfGam genes in CSA parasites on ring stages (white bars) and mature stages (black bars).E. Levels of H3K4 trimethylation at GBP130 and PfGam genes in CSA (white bars) and in CD36 ring parasites (black bars). The data are plotted as for Fig. 3.
Mentions: Particular histone methylation marks, such as H3K4 modifications, have been associated with transcriptional activity in other organisms. Trimethylated H3K4 is associated with active genes and dimethyl H3K4 correlates with a ‘permissive’ state of chromatin, in which genes are either active or potentially active (Schneider et al., 2004). We next investigated the role of these marks in var gene transcriptional control. ChIP analyses with antibodies against trimethylated H3K4 show that there is a prominent localized enrichment of trimethyl H3K4 at the 5′ flanking region of the var2csaON (Fig. 4A/C, A–C primers, white bars). There is also an enrichment of dimethylated H3K4 in the 5′ upstream region and early coding region of the var2csaON (Fig. 5A/C, A–E primers, white bars). Our results show that di- and trimethylated H3K4 marks differentiate active var members from stably repressed var gene members. To assess whether high levels of these modifications are a universal feature of active genes in P. falciparum, we analysed a single copy gene (GBP130) that is highly transcribed in asexual blood stage parasites (Figs 4D/E and 5D/E). The GBP130 gene contains significant amounts of di- and trimethylated H3K4. The silent PfGam gene carries only low levels of these marks. Thus, similar marks are associated with the transcription of single copy genes in asexual blood stage parasites. Genome wide analysis of the H3K4 methyl mark using ChIP-on-chip could reveal, at a more global level, actively transcribed genes of P. falciparum blood stage parasites.

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