RT Journal Article
SR Electronic
T1 Network-based integration of epigenetic landscapes unveils molecular programs underlying human T follicular helper cell differentiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.19.444859
DO 10.1101/2021.05.19.444859
A1 Vinay S Mahajan
A1 Syed A Rahman
A1 Vinayak V Viswanadham
A1 Grace J Yuen
A1 Na Sun
A1 Hamid Mattoo
A1 Shiv S Pillai
A1 Jishnu Das
YR 2021
UL http://biorxiv.org/content/early/2021/05/21/2021.05.19.444859.abstract
AB 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 StatementThe authors have declared no competing interest.