Divergent SAGA complexes shape the Toxoplasma transcriptome for lytic cycle progression and host interaction

Abstract

Histone acetylation governs Toxoplasma gondii gene expression, developmental plasticity and virulence, yet the organization and deployment of its acetyltransferase machinery remain poorly understood. Here, we show that T. gondii rewired this process using a plant-like system built around the acetyltransferase TgGCN5b, which differs from the typical SAGA complex found in other eukaryotes. Interactome and structural analyses reveal a modular assembly that integrates multiple acetyltransferase (GNAT) enzymes and chromatin-reader proteins carrying PHD and PZP domains and Apetala-related transcriptional regulators, an organization unique to apicomplexan parasites. TgGCN5b catalyzes a selective tri-site acetylation pattern on histone H3 at lysines 9, 14, and 18 that maintains open chromatin and sustains transcription of core metabolic, invasion, and virulence genes. Its conditional depletion disrupts these post-translational modifications, silencing key promoters and decoupling transcription from histone methylation. Genome-wide analyses further show that TgGCN5b functions independently of the MORC/HDAC3 repressive pathway, defining a distinct regulatory circuit that connects chromatin acetylation with gene expression and developmental transitions. These findings reveal that the SAGA complex has been evolutionarily reconfigured in T. gondii from a plant origin, yet featuring divergent and apicomplexan-specific feature, positioning TgGCN5b as a central regulator that links epigenetic control to parasite growth, adaptation, and virulence. Researchers show that the zoonotic parasite Toxoplasma gondii built a unique chromatin modifying complex to activate the genes that drive infection and virulence, revealing a potential weak spot for new treatments.