Abstract
T helper 17 (TH17) cells represent a pivotal adaptive cell subset involved in multiple immune disorders in mammalian species. Deciphering the molecular interactions regulating TH17 cell differentiation is particularly critical for novel drug target discovery designed to control maladaptive inflammatory conditions. Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling TH17 differentiation. From the network, we identified the Prdm1 gene encoding the B lymphocyte-induced maturation protein 1 as a crucial negative regulator of human TH17 cell differentiation. The results have been validated by perturbing Prdm1 expression on freshly isolated CD4+ naïve T cells: reduction of Prdm1 expression leads to augmentation of IL-17 release. These data unravel a possible novel target to control TH17 polarization in inflammatory disorders. Furthermore, this study represents the first in vitro validation of continuous time Bayesian networks as gene network reconstruction method and as hypothesis generation tool for wet-lab biological experiments.
Highlights
Regulation of those transcription factors that initiate and drive the development of TH17 cells remains unknown
Continuous time Bayesian networks (CTBNs) have been recently applied for the first time to the analysis of molecular data to investigate the regulatory interactions that characterize pathogenic versus non-pathogenic murine TH17 cells[21]
The network highlighted the gene Socs[3] as being the second major hub node of the process. Both genes are known to negatively regulate TH17 differentiation in murine tissues[23,24]. These findings suggests that negative regulators may exert a major control on TH17 differentiation process
Summary
The microarray measurements used to learn the regulatory network were taken at 10 different time-points over the span of 72 h following the initiation of the differentiation process. A novel model of conditional deletion in peripheral cells of PRDM1 revealed a positive role of this molecule on TH17 differentiation[28] This is in contrast with what emerged from previous studies, where the Prdm[1] gene was found to negatively regulate the secretion of IL-17 from murine TH17 cells[29]. SOCS3 plays a suppressive role in TH17 induction by negatively regulating STAT3 activation This specific well-known mechanism emerged from the inferred network (Fig. 2A), where a direct. Are placed, together with a number of other genes, at an intermediate level of the inferred network hierarchy This is consistent with these regulators not being known to act as early activators/repressors of the differentiation process. The network revealed how the major hubs SOCS3 and PRDM1 directly control the transcription factor BATF (Fig. 2B), which is a key positive regulator of the TH17 differentiation program. The network predicted BATF to control the expression of CXCR5, characterizing the TH17 differentiated subset, as is already known in the literature[36]
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