Sun Tzu’s ancient Chinese military treatise “The Art of War” placed knowing your enemy on a par with knowing yourself when facing battle. These wise words still resound today in the lab of Lubin Jiang (Institut Pasteur of Shanghai, Chinese Academy of Sciences, PR China) where researchers have employed CRISPR/Cas9 epigenome editing to forge a better understanding of their current enemy: Plasmodium falciparum, the parasite that causes the life-threatening disease malaria.
Specifically, the team developed an epigenome editing system composed of a nuclease-deficient Cas9 fused with histone acetylase or deacetylase modules to modulate gene expression in the malaria parasite. Employing this strategy, the authors hope to discover new targets for curative or preventative treatments in the battle against a disease that recently caused over 500,000 deaths in a single year.
Following the advice of Sun Tzu, the team soon set out to know their enemy by epigenetically editing it:
- The application of specific guide RNAs to guide dCas9 acetylase (PfGCN5) and deacetylase (PfSir2a) effectors to the transcriptional start sites of invasion-related gene promoters efficiently activated reticulocyte binding protein homolog 4 (rh4) expression and repressed erythrocyte binding protein 175 (
eba -175) expression, respectively- In vitro parasite assays employing human blood cells established that activation of rh4 expression induces invasive activity, while inhibition of
eba -175 expression reduces invasive activity
- Importantly, epigenome editing avoids the genomic disruption observed during the application of traditional CRISPR/Cas9 genome editing in P. falciparum
- In vitro parasite assays employing human blood cells established that activation of rh4 expression induces invasive activity, while inhibition of
- The team also employed their epigenome editing system to decipher the role of the essential PfSET1 gene, known to code for a histone methyltransferase
- Epigenetic editing suggests that PfSET1 regulates the expression of genes that control parasite maturation, thereby representing a potentially exciting target for the control of malaria infection or disease development
Previous applications of genome editing in malaria research aimed to generate disease-proof mosquitoes; however, the dCas9-based epigenome editing systems described in this study represent an exciting shift in strategy to an approach that regulates gene expression to tease apart parasite biology and hence develop new and effective strategies to face malaria on the battlefield.
Do you know your enemy well? Discover more on the potential of epigenome editing in the understanding, prevention, and treatment of malaria at PNAS, January 2019.