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Intragenomic Redistribution of Host Transcription Factor Binding With Toxoplasma Gondii Infection

Netha Ulahannan, Masako Suzuki, Claudia A. Simões-Pires, Zofia Wicik, N. Ari Wijetunga, Matthew McKnight Croken, Sanchari Bhattacharyya, Andrew D. Johnston, Yu Kong, Shahina B. Maqbool, Amit Verma, View ORCID ProfileJohn M. Greally
doi: https://doi.org/10.1101/132076
Netha Ulahannan
1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
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Masako Suzuki
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
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Claudia A. Simões-Pires
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
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Zofia Wicik
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
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N. Ari Wijetunga
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
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Matthew McKnight Croken
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
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Sanchari Bhattacharyya
3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461
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Andrew D. Johnston
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
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Yu Kong
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
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Shahina B. Maqbool
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
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Amit Verma
3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461
4Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461
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John M. Greally
2Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461
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  • ORCID record for John M. Greally
  • For correspondence: john.greally@einstein.yu.edu
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ABSTRACT

The intracellular pathogen Toxoplasma gondii modifies a number of host cell processes. The mechanisms by which T. gondii alters host gene expression are incompletely understood. This study focuses on how the regulators of gene expression in human host cells respond to T. gondii 24 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 with T. gondii is 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 that T. gondii infection influences transcriptional regulation through transcription factor re-targeting to modify the cis-regulatory landscape of the host nucleus.

AUTHOR SUMMARY The complex interactions between the intracellular pathogen Toxoplasma gondii and the host cell manifest as expression changes of host genes. T. gondii’s secreted 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 how T. gondii exerts 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 a T. gondii infection leads to an intragenomic redistribution of host transcription factor binding, with resulting effects on host gene expression.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 28, 2017.
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Intragenomic Redistribution of Host Transcription Factor Binding With Toxoplasma Gondii Infection
Netha Ulahannan, Masako Suzuki, Claudia A. Simões-Pires, Zofia Wicik, N. Ari Wijetunga, Matthew McKnight Croken, Sanchari Bhattacharyya, Andrew D. Johnston, Yu Kong, Shahina B. Maqbool, Amit Verma, John M. Greally
bioRxiv 132076; doi: https://doi.org/10.1101/132076
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Intragenomic Redistribution of Host Transcription Factor Binding With Toxoplasma Gondii Infection
Netha Ulahannan, Masako Suzuki, Claudia A. Simões-Pires, Zofia Wicik, N. Ari Wijetunga, Matthew McKnight Croken, Sanchari Bhattacharyya, Andrew D. Johnston, Yu Kong, Shahina B. Maqbool, Amit Verma, John M. Greally
bioRxiv 132076; doi: https://doi.org/10.1101/132076

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