Toxoplasma gondii AP2XII-2 Contributes to Transcriptional Repression for Sexual Commitment

Abstract

Toxoplasma gondii is a parasite that undergoes its sexual stage exclusively in feline intestines, making cats a major source of transmission. A better understanding of the proteins controlling the parasite’s life cycle stage transitions is needed for the development of new therapies aimed at treating toxoplasmosis and the transmission of the infection.

APlasmodium falciparumMORC protein complex modulates epigenetic control of gene expression through interaction with heterochromatin

“…Pf EELM2 was previously predicted as a Pf MORC interactor (Hillier et al 2019) and identified in a quantitative histone peptide pulldown to be consistently recruited to H2B.Z_K13/14/18a (Hoeijmakers et al 2019). Furthermore, we also detected numerous ApiAP2 transcription factors [ Pf AP2-G5, Pf AP2-O5, Pf AP2-I, PF3D7_1107800, PF3D7_0613800, PF3D7_0420300 and PF3D7_1239200] ( Table 1 ), similar to results reported both by Hillier et al and with Toxoplasma Tg MORC complex (Farhat et al 2020, Antunes et al 2023, Srivastava et al 2023). Pf AP2-G5 (PF3D7_1139300) and Pf AP2-O5 (PF3D7_1449500) were enriched 20.5- and 14.99-fold, respectively, suggesting that these factors are likely major components in-complex with Pf MORC.…”

“…Pf MORC association with chromatin remodelers has been shown (Bryant et al 2020), but how Pf MORC regulates gene expression in the asexual stage has not been evaluated. In T. gondii , the Tg MORC: Tg ApiAP2 complex acts as a transcriptional repressor of sexual commitment (Farhat et al 2020, Antunes et al 2023, Srivastava et al 2023). This study found that Pf MORC co-immunoprecipitates with several chromatin remodeling proteins and many ApiAP2 transcription factors.…”

“…Despite increasing evidence detailing ApiAP2 protein regulatory complexes (Santos et al 2017, Harris et al 2019, Hillier et al 2019, Hoeijmakers et al 2019, Farhat et al 2020, Josling et al 2020, Miao et al 2021, Antunes et al 2023, Srivastava et al 2023, Yuda et al 2023), the functional properties and specific interaction partners of many ApiAP2 TFs remain to be elucidated. A quantitative mass spectrometry-based analysis of the parasite protein interaction network has revealed links between ApiAP2 TFs and many chromatin remodelers, such as an extended Egl-27 and MTA1 homology 2 (EELM2) domain-containing proteins (PF3D7_0519800 and PF3D7_1141800), histone deacetylase protein 1 (HDAC1; PF3D7_0925700), and the microrchidia family protein Pf MORC (PF3D7_1468100) (Hillier et al 2019).…”

“…In the related apicomplexan parasite Toxoplasma gondii , Tg MORC functions as a repressor of sex-associated genes by recruiting the histone deacetylase protein Tg HDAC3 and forming heterogenous complexes with eleven ApiAP2 TFs (Farhat et al 2020). To date, only two Tg MORC:HDAC3 complexes have been characterized, including a Tg AP2XII-2:HDAC3 complex and a heterotrimeric Tg AP2XII-1:AP2XI-2:HDAC3 complex (Antunes et al 2023, Srivastava et al 2023).…”

DNA sequence context and the chromatin landscape differentiate sequence-specific transcription factor binding in the human malaria parasite,Plasmodium falciparum

“…The absence of overlapping in vivo binding for AP2-LT and AP2-HC 89 TFs is supported by recent studies that identified AP2-HC complexed with PfHP1 89 at heterochromatic regions, while AP2-LT is a component of the putative PfSAGA transcriptional co-activating complex which is only found in euchromatic regions. While the specific role of PF3D7_0420300 as a TF during P. falciparum asexual blood stage development remains unknown, a previous publication identified its interaction with PfMORC 120 , a putative repressive complex component highly characterized in metazoans [121][122][123][124][125][126][127][128] and recently in Toxoplasma gondii 129,130 . Therefore, we anticipate that a PF3D7_0420300:PfMORC complex would bind genomic regions not bound by AP2-LT or AP2-HC.…”