Intragenomic Redistribution of Host Transcription Factor Binding With Toxoplasma Gondii Infection
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ABSTRACTThe intracellular pathogenToxoplasma gondiimodifies a number of host cell processes. The mechanisms by whichT. gondiialters host gene expression are incompletely understood. This study focuses on how the regulators of gene expression in human host cells respond toT. gondii24 hours following infection to cause specific patterns of transcriptional dysregulation. The most striking finding was the altered landscape of transposase-accessible chromatin by infection. We found both gains and losses of loci of open chromatin enriched in proximity to transcriptionally altered genes. Both DNA sequence motif analysis at the loci changing chromatin accessibility and network analysis of the genes with transcription and regulatory changes implicate a central role for the AP-1 transcription factor. We validated the redistribution of AP-1 in the host genome using chromatin immunoprecipitation studies of the c-Fos component of AP-1. As infection withT. gondiiis associated with the cell failing to progress through the cell cycle, all of the changes observed occur in the absence of cell division and within 24 hours, an insight into the dynamism of these transcriptional regulatory events. We conclude thatT. gondiiinfection influences transcriptional regulation through transcription factor re-targeting to modify thecis-regulatory landscape of the host nucleus.AUTHOR SUMMARYThe complex interactions between the intracellular pathogenToxoplasma gondiiand the host cell manifest as expression changes of host genes.T. gondiissecreted effectors have been extensively studied and include factors that influence the properties of transcription factors, resulting in post-translational modifications and changes in intracellular localization. To gain insights into howT. gondiiexerts specific influences on host transcriptional regulation, we used genome-wide approaches to study gene expression, cytosine modifications, and chromatin structure of the host cell 24 hours after infection. The greatest insights were gained from the mapping of loci of transposase-accessible chromatin, revealing a consistently altered pattern of a subset of loci becoming inaccessible, with the simultaneous acquisition of a new set of infection-associated loci of open chromatin. The sequences at these loci were enriched for certain transcription factor binding motifs, in particular that of AP-1, the transcription factor formed by c-Jun and c-Fos heterodimers. Network analysis revealed a central role for c-Jun and c-Fos in the infection-associated perturbations, prompting a chromatin immunoprecipitation approach that confirmed the redistribution of c-Fos in infected cells. We conclude that aT. gondiiinfection leads to an intragenomic redistribution of host transcription factor binding, with resulting effects on host gene expression.
Ulahannan, N., Suzuki, M., Simes-Pires, C. A., Wicik, Z., Wijetunga, N. A., Croken, M. M., ... Greally, J. M.
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Ulahannan, Netha||Suzuki, Masako||Simões-Pires, Claudia A||Wicik, Zofia||Wijetunga, N Ari||Croken, Matthew McKnight||Bhattacharyya, Sanchari||Johnston, Andrew D||Kong, Yu||Maqbool, Shahina B||Verma, Amit||Greally, John M
