Nuclear non-coding RNAs are transcribed from the centromeres of Plasmodium falciparum and are associated with centromeric chromatin.

Non-coding RNAs (ncRNAs) play an important role in a variety of nuclear processes, including genetic imprinting, RNA interference-mediated transcriptional repression, and dosage compensation. These transcripts are thought to influence chromosome organization and, in some cases, gene expression by directing the assembly of specific chromatin modifications to targeted regions of the genome. In the malaria parasite Plasmodium falciparum, little is known about the regulation of nuclear organization or gene expression, although a notable scarcity of identifiable transcription factors encoded in its genome has led to speculation that this organism may be unusually reliant on chromatin modifications as a mechanism for regulating gene expression. To study the mechanisms that regulate chromatin structure in malaria parasites, we examined the role of ncRNAs in the assembly of chromatin at the centromeres of P. falciparum. We show that centromeric regions within the Plasmodium genome contain bidirectional promoter activity driving the expression of short ncRNAs that are localized within the nucleus and appear to associate with the centromeres themselves, strongly suggesting that they are central characters in the maintenance and function of centromeric chromatin. These observations support the hypothesis that ncRNAs play an important role in the proper organizational assembly of chromatin in P. falciparum, perhaps compensating for a lack of both regulatory transcription factors and RNA interference machinery.

Human PAD4 regulates histone arginine methylation levels via demethylimination.

Methylation of arginine (Arg) and lysine residues in histones has been correlated with epigenetic forms of gene regulation. Although histone methyltransferases are known, enzymes that demethylate histones have not been identified. Here, we demonstrate that human peptidylarginine deiminase 4 (PAD4) regulates histone Arg methylation by converting methyl-Arg to citrulline and releasing methylamine. PAD4 targets multiple sites in histones H3 and H4, including those sites methylated by coactivators CARM1 (H3 Arg17) and PRMT1 (H4 Arg3). A decrease of histone Arg methylation, with a concomitant increase of citrullination, requires PAD4 activity in human HL-60 granulocytes. Moreover, PAD4 activity is linked with the transcriptional regulation of estrogen-responsive genes in MCF-7 cells. These data suggest that PAD4 mediates gene expression by regulating Arg methylation and citrullination in histones.