The malaria parasite Plasmodium falciparum histones: Organization, expression, and acetylation

Fan

International Journal for Parasitology

et al. 2008

Self Cite

124

148

Dynamic histone lysine methylation, regulated by methyltransferases and demethylases, plays fundamental roles in chromatin structure and gene expression in a wide range of eukaryotic organisms. A large number of SET-domain-containing proteins make up the histone lysine methyltransferase (HKMT) family, which catalyzes the methylation of different lysine residues with relatively high substrate specificities. Another large family of Jumonji C (JmjC)-domaincontaining histone lysine demethylases (JHDMs) reverses histone lysine methylation with both lysine site and methyl-state specificities. Through bioinformatic analysis, at least nine SET domain-containing genes were found in the malaria parasite Plasmodium falciparum and its sibling species. Phylogenetic analysis separated these putative HKMTs into five subfamilies with different putative substrate specificities. Consistent with the phylogenetic subdivision, methyl marks were found on K4, K9 and K36 of histone H3, and K20 of histone H4 by site-specific methyl-lysine antibodies. In addition, most SET domain genes and histone methyl-lysine marks displayed dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites. Furthermore, the malaria parasite and other apicomplexan genomes also encode JmjC-domaincontaining proteins that may serve as histone lysine demethylases. Whereas prokaryotic expression of putative active domains of four P. falciparum SET proteins did not yield detectable HKMT activity towards recombinant P. falciparum histones, two protein domains expressed in vitro in a eukaryotic system showed HKMT activities towards H3 and H4, respectively. With the discovery of these Plasmodium SET-and JmjC-domain genes in the malaria parasite genomes, future efforts will be directed towards elucidation of their substrate specificities and functions in various cellular processes of the parasites.

Section: Parasite Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Histone lysine methyltransferases and demethylases in Plasmodium falciparum

Fan

International Journal for Parasitology

et al. 2008

Self Cite

124

148

“…56) In fact, there are many unassigned genes in P. falciparum, and many aspects of gene regulation in P. falciparum are unusual and poorly understood, 38,39,54,57) e.g. extensive histone modification 58) and combinatorial gene regulation. 59) Even though 88% of all predicted genes are expressed at least once in the life cycle, and more than half appear to be constitutively expressed, 60) the function of 60% of the predicted open reading frames is unknown, suggesting an important ongoing role for transcriptomics in malaria research.…”

Section: Transcriptomicsmentioning

confidence: 99%

Enlistment of omics technologies in the fight against malaria: Panacea or Pandora's Box?

et al. 2006

Plasmodium spp, the causative agent of malaria, imposes an enormous cost on the developing world. Current methods are inadequate for long-term management and eradication, and new treatments are desperately needed. The modern arsenal of "omics" technologies appears to offer a promising approach to engineering a long-term solution to malaria. However, because funding for malaria research is chronically limited, the potential results of omics methodologies must be examined to address whether the investment is justified. This review provides an overview of a suite of omics-related technologies in terms of their potential contribution to the field of malaria research.

Proc. Natl. Acad. Sci. U.S.A.

“…Thus far, no evidence for DNA methylation has been observed in P. falciparum. There are eight histone genes in P. falciparum that allow formation of a basic unit of chromatin, the nucleosome, where histone modifications and nucleosome remodeling occur (9). Histone modifications exist in P. falciparum.…”

mentioning

confidence: 99%

Epigenetic control of the variable expression of aPlasmodium falciparumreceptor protein for erythrocyte invasion

Jiang

López-Barragán

Jiang

et al. 2010

Plasmodium falciparum can invade erythrocytes by redundant receptors, some of which have variable expression. A P. falciparum clone Dd2 requiring erythrocyte sialic acid for invasion can be switched to a sialic acid-independent progeny clone Dd2NM by growing the Dd2 clone with neuraminidase-treated erythrocytes. The RH4 gene is transcriptionally up-regulated in Dd2NM compared to Dd2, despite the absence of DNA changes in and around the gene. We determined the epigenetic modifications around the transcription start site (TSS) at the time of expression of RH4 in Dd2NM (44 h) and at an earlier time when RH4 is not expressed (24 h). At 44 h, the occupancy of the +1 nucleosome site downstream of the TSS of the active RH4 gene in Dd2NM was markedly reduced compared to Dd2; no difference was observed at 24 h. At 44 h, histone modifications associated with up-regulation were positively correlated to the active RH4 gene of Dd2NM compared to Dd2; no differences were observed at 24 h. Histone H3K9 trimethylation (a marker for silencing) was higher in Dd2 than Dd2NM along the 5′-UTRs of the RH4 gene at both 44 and 24 h. Our data indicate that the failure of Dd2 to express the sialic acid-independent invasion receptor gene RH4 is associated with the epigenetic silencing mark H3K9 trimethylation present throughout the cycle.epigenetic mark | histone modification | nucleosome T he causative agent for the most severe human malaria, Plasmodium falciparum, invades erythrocytes by multiple redundant pathways (1, 2). Two P. falciparum receptor protein families, the Duffy Binding-Like (DBL) family and the Reticulocyte Homology (RH) family, play key roles in parasite invasion (1). A unique parasite clone Dd2 that initially invaded erythrocytes requiring sialic acid was able to be selected to a sialic acid-independent clone (Dd2NM) after maintaining the parental clone Dd2 in culture with neuraminidase-treated erythrocytes (3). Comparing the gene expression of Dd2 and Dd2NM, only RH4 and the DBL pseudogene PEBL, are transcriptionally up-regulated in Dd2NM (4, 5). The two genes are located contiguously on P. falciparum chromosome 4 and transcribed in opposite directions. The sequences of the exons and introns of the two genes, the 1.8 kb between the two ORFs, and 1.1 kb of genomic DNA 3′ to each gene's coding region were identical in Dd2 and Dd2NM (4), suggesting that transcription of the two genes is epigenetically regulated.Because a transcription-associated histone acetyltransferase from Tetrahymena was identified in 1996 (6), diverse histone modifications on different amino acid residues in the core histones have been discovered to play important roles in transcriptional regulation in various eukaryotic organisms (7). This led to a hypothesis of a program of epigenetic marks consisting of covalent histone tail modifications, chromatin remodeling, noncoding RNA, and DNA methylation (8). Thus far, no evidence for DNA methylation has been observed in P. falciparum. There are eight histone genes in P. falciparum that allow formation of ...