A SAGA-like AP2-P-ARP1-GCN5 transcriptional complex targets pathogenesis-associated genes during the blood-stage development of Babesia gibsoni

Babesiosis is an increasingly recognized tick-borne zoonosis. The asexual blood stage of its causative agent, Babesia, drives pathological damages in the host and can cause severe or fatal human infections. Nevertheless, the transcriptional regulatory mechanisms that control this developmental stage remain poorly characterized. Here, we identified a novel ApiAP2 transcription factor (AP2-P; pathogenesis), which is essential in the blood-stage development of B. gibsoni. Nuclear import of AP2-P is inhibited by ivermectin, which is likely mediated via the IMPα/β pathway. Importantly, AP2-P forms a SAGA-like complex with the histone acetyltransferase GCN5 and a novel AP2-P related protein 1 (ARP1). Conditional knockdown of ARP1 or GCN5 results in reduced parasite growth rates accompanied by alterations in expression profiles and chromatin accessibility of pathogenesis-related genes. ChIP-seq data indicate that the complex associates with both euchromatic regions marked by H3K9ac and heterochromatic regions marked by H3K9me3, and it also targets many pathogenic genes by recognizing specific DNA motif, including those involved in invasion, antigenic variation, drug resistance, and sexual-stage development. Notably, normal genomic distribution pattern of AP2-P likewise depends on ARP1 or GCN5. Collectively, our study suggests a SAGA-like epigenetic module responsible for pathogenesis of Babesia gibsoni during asexual blood stage. This study characterizes a novel SAGA-like epigenetic regulatory module in Babesia gibsoni, composed of the ApiAP2 transcription factor AP2-P, ARP1 and histone acetyltransferase GCN5. This complex modulates chromatin accessibility and binds specific genomic motifs to control the expression of genes involved in parasite invasion, antigenic variation, drug resistance and stage conversion, critically supporting parasite blood-stage growth and pathogenicity.