iScienceOct 10, 2026

Inducible dCas12a system expands gene control tools for studying malaria parasite Plasmodium falciparum

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 11, 2026

Abstract

Inducible dead Cas12a-based CRISPR interference/activation systems were developed for Plasmodium falciparum.

Unlike dCas9, dCas12a can recognize T-rich PAMs, allowing for more flexible gene regulation.
The system can process a single transcript into multiple sgRNAs, enabling multiplexed regulation of genes.
Functional validation showed that single sgRNAs effectively mediated gene regulation.
Multiplexed sgRNA arrays enhanced the activities of CRISPR interference.
Conditional repression of the histone methyltransferase gene PfSET7 impaired parasite multiplication.

Simplified

We developed inducible dead Cas12a (dCas12a)-based CRISPR interference/activation (CRISPRi/a) systems for Plasmodium falciparum, expanding the gene regulation toolkit beyond dCas9. Our previous systems fused dCas9 to the catalytic domains of PfSir2a or PfGCN5 under DiCre/loxP regulon, enabling conditional gene regulation but remaining constrained by Cas9's NGG protospacer adjacent motif (PAM) requirement. Unlike dCas9, dCas12a recognizes T-rich PAMs and processes a single transcript into multiple sgRNAs via its RNase activity, allowing multiplexed regulation of one or multiple genes. Functional validation targeting EBA175 and ATG18 demonstrated that single sgRNAs mediated CRISPRi/a's active gene regulation, while multiplexed sgRNA arrays enhanced CRISPRi activities. Using this platform, we showed that conditional repression of the histone methyltransferase gene PfSET7 impairs schizont egress and merozoite invasion, highlighting its critical role in parasite multiplication, consistent with its Toxoplasma homolog TgADTM1. Altogether, these results establish dCas12a-based CRISPRi/a as a versatile platform for conditional and multiplexed gene regulation in P. falciparum.

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Inducible dCas12a system expands gene control tools for studying malaria parasite Plasmodium falciparum

Abstract

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