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Novel Method of Transcription Regulation Seen in Malaria Parasite

In trying to understand how the human malaria parasite (Plasmodium falciparum) multiplies in red blood cells, a research team has discovered that a kind of "histone crash" takes place--a massive breakdown of the chromatin architecture that explains how the parasite can extensively and rapidly replicate its DNA and coding genes. "If this mechanism can be stopped," said Dr. Karine Le Roch, an assistant professor of cell biology and neuroscience at the University of California-Riverside, and senior author of the report, "Plasmodium replication would cease or be severely inhibited, thus controlling the spread of malaria." "Dr. Le Roch's findings document a global mechanism mediating significant changes in gene expression as the parasites transition through developmental stages in the human hosts," said Dr. Anthony A. James, a distinguished professor of microbiology & molecular genetics and molecular biology & biochemistry at the University of California-Irvine, who was not involved in the research. "As well as being a major basic discovery, this provides a basis for probing the mechanisms for novel drug development." The current study was spurred, in part, by an earlier observation that, in Plasmodium falciparum, specific transcription factors are apparently under-represented relative to the size of the parasite’s genome, and by the fact that mechanisms underlying transcriptional regulation in Plasmodium have remained controversial. “Our results demonstrate that the processes driving gene expression in Plasmodium challenge the classical eukaryotic model of transcriptional regulation occurring mostly at the transcription initiation level. We found in our experiments that histones are massively evicted everywhere in the Plasmodium genome, resulting in most of the Plasmodium genes to be transcribed at once," said Dr. La Roch.

The researchers postulated that chromatin structure and nucleosome turnover control massive transcription during the Plasmodium’s cycle in the red blood cell. This contrasts sharply with the targeted chromatin reorganization seen in most eukaryotes. "If we can find a candidate enzyme that can regulate this massive histone eviction, we could halt or greatly limit Plasmodium replication," Dr. La Roch said.

In the cells of eukaryotes, such as the unicellular Plasmodium and humans, DNA strands, which can be as long as two meters, are closely packed to fit into the cell's tiny nucleus. Huge complex proteins called nucleosomes facilitate this DNA compaction so that eventually the DNA is coiled in an ordered manner to form chromosomes. Made up of histones, the nucleosomes are repeating units around which the double helix of DNA gets wrapped and vast amounts of genetic information get organized.

For cell multiplication to occur, genes in a DNA strand need to first be transcribed and translated into protein. For transcription to take place, the nucleosomes must first be removed (evicted), a process that opens up the DNA strand to give special "transcription factors" full access to the genes. The transcription factors then help convert these genes into mRNA, which is then translated into protein.

While in humans such eviction of nucleosomes is specific to only some sections of the DNA strand and performed only when needed; in Plasmodium, the situation is vastly different. The experiments conducted by Dr. La Roch’s team show that 18 hours after Plasmodium enters a red blood cell, a huge eviction of nucleosomes occurs in the Plasmodium DNA. Gene transcription throughout the genome follows and after multiplication into up to 32 daughter cells, the newly-formed parasites are ready to exit the red blood cell and invade new ones about 18 hours later

The new research by Dr. La Roch’s team was reported in the February 2010 issue of Genome Research. [Press release] [Genome Research abstract]