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Heterochromatin formation in bistable chromatin domains controls the epigenetic repression of clonally variant Plasmodium falciparum genes linked to erythrocyte invasion.
Mol Microbiol. 2011 Apr; 80(2):391-406
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10 Jun 2011
New Finding
DOI: 10.3410/f.11099956.12058054
This is an important paper on mechanisms of expression of alternative variant ligands at the merozoite stage of malaria parasites that invade erythrocytes. Results are relevant also for broader understanding of epigenetic regulation in parasites, complementing independent work on other variant gene...Continue reading
This is an important paper on mechanisms of expression of alternative variant ligands at the merozoite stage of malaria parasites that invade erythrocytes. Results are relevant also for broader understanding of epigenetic regulation in parasites, complementing independent work on other variant gene families and transcriptome-wide approaches.
The study focuses on 3 merozoite stage-specific genes showing alternative expression states reflected in transcriptional variation among different cultured subclones of a parasite clone (3D7). It characterises upstream sequences required for promoter activity, nucleosome positions, and relevant histone modifications. Results strongly indicate that trimethylation of lysine at position 9 of histone H3 (H3K9me3) is a marker of heterochromatin formation responsible for locus-specific transcriptional repression, whereas acetylation of the residue is a marker of activation. These alternative states are stable throughout the 48 hour asexual blood cycle of development in different respective parasite subclones, so appear to 'bookmark' the expression from one asexual generation to the next until relevant nucleosome positioning and transcription becomes apparent at the late schizont/merozoite stage. This fits a model of 'bistable chromatin' with a low (although not yet quantified) switch rate between imprinted alternative states. The mechanism and determinants of such switching need to be investigated, as this has major relevance to parasite biology and adaptation. Preliminary evidence identified a probable site of a barrier insulator between neighbouring chromatin domains, which prevents spreading of the heterochromatin but rather allows one gene to remain stably activated while a neighbouring gene is repressed.
The study focuses on 3 merozoite stage-specific genes showing alternative expression states reflected in transcriptional variation among different cultured subclones of a parasite clone (3D7). It characterises upstream sequences required for promoter activity, nucleosome positions, and relevant histone modifications. Results strongly indicate that trimethylation of lysine at position 9 of histone H3 (H3K9me3) is a marker of heterochromatin formation responsible for locus-specific transcriptional repression, whereas acetylation of the residue is a marker of activation. These alternative states are stable throughout the 48 hour asexual blood cycle of development in different respective parasite subclones, so appear to 'bookmark' the expression from one asexual generation to the next until relevant nucleosome positioning and transcription becomes apparent at the late schizont/merozoite stage. This fits a model of 'bistable chromatin' with a low (although not yet quantified) switch rate between imprinted alternative states. The mechanism and determinants of such switching need to be investigated, as this has major relevance to parasite biology and adaptation. Preliminary evidence identified a probable site of a barrier insulator between neighbouring chromatin domains, which prevents spreading of the heterochromatin but rather allows one gene to remain stably activated while a neighbouring gene is repressed.
Disclosures
None declared
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Conway D: F1000Prime Recommendation of [Crowley VM et al., Mol Microbiol 2011, 80(2):391-406]. In F1000Prime, 10 Jun 2011; DOI: 10.3410/f.11099956.12058054. F1000Prime.com/11099956#eval12058054
F1000Prime Recommendations, Dissents and Comments for [Crowley VM et al., Mol Microbiol 2011, 80(2):391-406]. In F1000Prime, 22 May 2013; F1000Prime.com/11099956
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Clonally variant gene expression is a common survival strategy used by many pathogens, including the malaria parasite Plasmodium falciparum. Among the genes that show variant expression in this parasite are several members of small gene families linked to erythrocyte invasion, including the clag and eba families. The active or repressed state of these genes is clonally transmitted by epigenetic mechanisms. Here we characterized the promoters of clag3.1, clag3.2 and eba-140, and compared nuclease accessibility and post-translational histone modifications between their active and repressed states. Activity of these promoters in an episomal context is similar between parasite subclones characterized by different patterns of expression of the endogenous genes. Variant expression is controlled by the euchromatic or heterochromatic state of bistable chromatin domains. Repression is mediated by H3K9me3-based heterochromatin, whereas the active state is characterized by H3K9ac. These marks are maintained throughout the asexual blood cycle to transmit the epigenetic memory. Furthermore, eba-140 is organized in two distinct chromatin domains, probably separated by a barrier insulator located within its ORF. The 5' chromatin domain controls expression of the gene, whereas the 3' domain shares the chromatin conformation with the upstream region of the neighbouring phista family gene, which also shows variant expression.
© 2011 Blackwell Publishing Ltd.
DOI: 10.1111/j.1365-2958.2011.07574.x
PMID: 21306446
