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Network-based integration of epigenetic landscapes unveils molecular programs underlying human T follicular helper cell differentiation

Vinay S Mahajan, Syed A Rahman, Vinayak V Viswanadham, Grace J Yuen, Na Sun, Hamid Mattoo, Shiv S Pillai, View ORCID ProfileJishnu Das
doi: https://doi.org/10.1101/2021.05.19.444859
Vinay S Mahajan
1Ragon Institute of MGH, MIT and Harvard, Cambridge, MA
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Syed A Rahman
2Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA
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Vinayak V Viswanadham
1Ragon Institute of MGH, MIT and Harvard, Cambridge, MA
3Department of Biomedical Informatics, Harvard Medical School, Boston, MA
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Grace J Yuen
1Ragon Institute of MGH, MIT and Harvard, Cambridge, MA
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Na Sun
1Ragon Institute of MGH, MIT and Harvard, Cambridge, MA
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Hamid Mattoo
1Ragon Institute of MGH, MIT and Harvard, Cambridge, MA
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Shiv S Pillai
1Ragon Institute of MGH, MIT and Harvard, Cambridge, MA
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  • For correspondence: jishnu@pitt.edu pillai@helix.mgh.harvard.edu
Jishnu Das
2Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA
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  • ORCID record for Jishnu Das
  • For correspondence: jishnu@pitt.edu pillai@helix.mgh.harvard.edu
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Abstract

T follicular helper (Tfh) cells play a critical role in T-dependent humoral immune responses. While genetic programs controlling Tfh cell differentiation have been extensively studied using murine models, studies in humans have been hampered by the lack of a robust in vitro differentiation system for Tfh cells. We characterized epigenomic landscapes across stages of Tfh cell differentiation in a healthy human tonsil using ATAC-Seq and CUT&RUN for selected histone modifications. We combined these epigenomic datasets and integrated them with the reference human protein interactome using a novel network propagation approach. Our approach uncovered subnetworks integral to Tfh cell differentiation. These subnetworks captured known Tfh cell drivers to a greater extent than conventional gene-centric analyses would, and also revealed novel modules that may be required for Tfh cell differentiation. We find that human Tfh cell subnetworks are functionally associated with specific immune signaling cascades including cytokine receptor driven pathways. Analyses of transcriptomic data revealed that in addition to these immune pathways being significantly dysregulated in severe COVID-19, the corresponding Tfh cell subnetworks are also transcriptionally perturbed to a similar extent. This provides a molecular mechanistic basis for the previously observed impaired Tfh cell differentiation and loss of germinal centers in severe COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

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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 May 21, 2021.
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Network-based integration of epigenetic landscapes unveils molecular programs underlying human T follicular helper cell differentiation
Vinay S Mahajan, Syed A Rahman, Vinayak V Viswanadham, Grace J Yuen, Na Sun, Hamid Mattoo, Shiv S Pillai, Jishnu Das
bioRxiv 2021.05.19.444859; doi: https://doi.org/10.1101/2021.05.19.444859
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Network-based integration of epigenetic landscapes unveils molecular programs underlying human T follicular helper cell differentiation
Vinay S Mahajan, Syed A Rahman, Vinayak V Viswanadham, Grace J Yuen, Na Sun, Hamid Mattoo, Shiv S Pillai, Jishnu Das
bioRxiv 2021.05.19.444859; doi: https://doi.org/10.1101/2021.05.19.444859

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