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Background  In the human malaria parasites  Plasmodium falciparum , histone modifications have been implicated in the transcriptional regulation. The acetylation and methylation status of the histones have been linked with transcriptional regulation of the parasite surface virulence factors as well as other genes with stage specific expression. In  P. falciparum  as well as other eukaryotes, different histone modifications were found to be compartmentalized to distinct regions in the nuclei. This compartmentalization is believed to be one of the main prerequisites for their function in epigenetic regulation of gene expression.    Methodology/Principal Findings  Here we investigate intracellular distributions of five previously uncharacterized histone modifications including histone 4 acetylation on lysine residue 5 (H4K5Ac), H4K8Ac, H3K9Ac, H4Ac4 and H3K9Me1 during the asexual developmental stages. With the exception of H3K9Me1, the modified histones were localized to the nuclear periphery. This provides a strong indication that the  P. falciparum  nuclear periphery is one of the most active regions in epigenetic regulation of gene expression. Interestingly, H3K9Me1 is not associated with the nuclei but instead resides in the parasitophorous vacuole (PV), the double membrane compartments surrounding the parasite cell within the host erythrocyte. In this compartment, H3K9Me1 partially co-localizes with Etramp proteins. The localization of H3K9Me1 in the PV is conserved in the other species including  P. yoelii  and  P. vivax .    Conclusions  Similar to other eukaryotes, the periphery of the  P. falciparum  nuclei is likely one of the most active areas in epigenetic regulation of gene expression involving multiple histone modifications. On the other hand, H3K9Me1 evolved a new function that is linked with the PV. This functional role appears to be evolutionarily conserved in  Plasmodium  species.

A Moonlighting Function of Plasmodium falciparum Histone 3, Mono-Methylated at Lysine 9?