Mohamed-Ali Hakimi
Institute for Advanced Biosciences (IAB), Grenoble
Abstract : Sexual reproduction of Toxoplasma gondii, confined to the felid gut, remains largely uncharted owing to ethical concerns regarding the use of cats as model organisms. Chromatin modifiers dictate the developmental fate of the parasite during its multistage life cycle, but their targeting to stage-specific cistromes is poorly described. Emerging evidence suggests that Toxoplasma’s developmental trajectories are orchestrated by an interconnected network of transcriptional switches and chromatin remodeling mechanisms, acting in concert to ensure robust stage transitions. We will outline an updated epigenetic framework for stage transitions and highlight the functional synergy between an ISWI-family chromatin remodeler (Pachano et al. 2025) and the MORC/HDAC3 repressor complex (Farhat et al. 2020), which together modulate chromatin accessibility to maintain or shift developmental states. We also spotlight recent findings showing that simultaneous depletion of AP2XII-1 and AP2XI-2 transcription factors reactivates the presexual program in vitro, eliminating the need for cat hosts and allowing ethical, scalable exploration of sexual stages (Antunes et al. 2024). These findings provide a powerful conceptual and experimental framework for dissecting parasite transmission and persistence and have far-reaching implications for the biology of other parasites in the phylum.
Related references:
Pachano B, Farhat DC, Shahinas M, von Velsen J, Corrao C, Belmudes L, de Bock PJ, Mas C, Couté Y, Bowler MW, Bougdour A, Swale C and Hakimi MA. An ISWI-related chromatin remodeler regulates stage-specific gene expression in Toxoplasma gondii. Nat Microbiol. 2025 May;10(5):1156-1170.
Antunes AV, Shahinas M, Swale C, Farhat DC, Ramakrishnan C, Bruley C, Cannella D, Robert MG, Corrao C, Coute Y, Hehl AB, Bougdour A, Coppens I and Hakimi MA. In vitro production of cat-restricted Toxoplasma pre-sexual stages. Nature. 2024 Jan;625(7994):366-376.
Farhat DC, Swale C, Dard C, Cannella D, Ortet P, Barakat M, Sindikubwabo F, Belmudes L, De Bock PJ, Couté Y, Bougdour A and Hakimi MA. A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment. Nat Microbiol. 2020 5(4):570-583.
