The phylum of apicomplexan parasites is a large and diverse clade of protists that is responsible for significant diseases of humans and animals [1]. Comparative studies with the closely related Chromera velia have shown that apicomplexans evolved from free-living phototrophic algae, experiencing gene reduction and adaptation to engage in parasitism 2••, 3. As single-celled obligate parasites, apicomplexans have developed multiple morphologically distinct forms adapted to asexual replication or sexual recombination in one or more host species. Early-branching apicomplexans such as gregarines (e.g. Gregarina niphandrodes) or cryptosporidia (e.g. Cryptosporidium parvum) undergo both sexual and asexual replication in a single host. By contrast, sexual and asexual replication of other apicomplexans, such as Haemosporida (e.g. Plasmodium spp.) and Piroplasmida (e.g. Babesia spp. and Theileria spp.), require alternating infections of vertebrate and invertebrate hosts, where asexual and sexual replication take place, respectively [4]. Other groups show greater flexibility. For example, the completion of the coccidian life cycle can be achieved in a single host (e.g. Eimeria tenella infections in poultry) or involves multiple host species (e.g. Toxoplasma gondii specifically exhibits sexual replication in the intestinal epithelium of felids) [5]. In order to maintain this intricate life cycle and adapt to constantly changing surroundings, apicomplexan parasites rely on distinct gene-expression programs that tune responses to varying nutrient availability and other environmental cues. For example, Plasmodium falciparum induces a protective heat-shock response during the febrile episodes of its hosts by changing the transcript levels of over 300 genes [6]. In addition, species such as Plasmodium vivax or T. gondii form dormant cell types that mediate persistence for months or years before reactivation 7, 8. Therefore, the ability of apicomplexan parasites to colonize their hosts, evade immune responses, and transmit to new hosts requires the coordinated action of numerous transcriptional regulators 9, 10, 11.

Transcriptional regulation plays a crucial role in orchestrating gene-expression changes across apicomplexan life cycles 12, 13, 14••, 15, 16. Several features of the apicomplexan transcriptional machinery are shared with other eukaryotes, including factors associated with the RNA polymerase, such as the TATA-binding protein (TBP) or TBP-associated factors, and basal transcription factors (TFs) that form the preinitiation complex at core promoter elements [17]. The accessibility of promoter elements is determined by chromatin structure, which can be regulated by chromatin-remodeling complexes and histone-modifying enzymes. In apicomplexan parasites, both conserved and unique histone modifications have been detected [18]. Combinations of histone marks and histone variants have been associated with transcriptional activation, repression, and elongation. Consequently, histone modifications are under the strict control of several histone modifiers [9]. In T. gondii, the histone deacetylase HDAC3 interacts with a unique version of the MORC chromatin remodeler and other factors to repress sexual-stage transcripts. The MORC–HDAC3 complex and other chromatin remodelers are often guided to specific DNA motifs, directly or indirectly, through proteins harboring DNA-binding domains 19, 20. This makes DNA-binding proteins essential for orchestrating complex gene-expression networks, ensuring proper cellular development, differentiation, and responses to environmental cues.

Apicomplexan parasites have lost many conventional eukaryotic DNA-binding proteins and their distinctive binding sites such as Forkhead box family TFs or basic helix–loop–helix TFs [21]. However, the ratio of TFs to proteome size is comparable between apicomplexans and other eukaryotes, due to the lineage-specific expansion of a single class of DNA-binding proteins: the plant-like Apetala2/ethylene response factor (AP2) TFs [22]. Many TFs exhibit lineage-specific expansions, suggesting considerable variability in transcriptional regulation and gene expression even among closely related eukaryotic lineages 21, 23. Apicomplexan AP2 (ApiAP2) domain–containing proteins (previously reviewed in Ref. [24]) are important drivers of differentiation, parasite virulence, and cell cycle regulation 25, 26, 27. For example, AP2-G is the master regulator of sexual differentiation in P. falciparum, while AP2IX-5 is a vital regulator of asexual cell division in T. gondii 25, 26. In addition to ApiAP2 domain–containing proteins, apicomplexan genomes encode various smaller families of DNA-binding proteins. These include Zn finger, myeloblastosis (Myb), Forkhead-associated, and high-mobility-group (HMG) DNA-binding domain–containing protein families [21]. Although some of these putative TFs have crucial functions throughout the parasite life cycle, most remain functionally and mechanistically unexplored. This review comprehensively explores the role of Myb domain–containing proteins (Mybs) in apicomplexan parasites to examine their structural features, functional diversity, and regulatory mechanisms. In so doing, we hope to highlight their emerging roles in apicomplexan gene expression.