Optimized logic rules reveal interferon‐γ‐induced modes regulated by histone deacetylases and protein tyrosine phosphatases

Abstract

The pro-inflammatory cytokine interferon-γ (IFN-γ) is critical for activating innate and adaptive immunity against tumours and intracellular pathogens. Interferon-γ is secreted at the fetal-maternal interface in pregnant women and mice. The outer layer of the placenta in contact with maternal blood is composed of semi-allogeneic trophoblast cells, which constitute the fetal component of the fetal-maternal interface. The simultaneous presence of pro-inflammatory IFN-γ and trophoblast cells at the fetal-maternal interface appears to represent an immunological paradox, for trophoblastic responses to IFN-γ could potentially lead to activation of maternal immunity and subsequent attack of the placenta. However, our previous studies demonstrate that IFN-γ responsive gene (IRG) expression is negatively regulated in human and mouse trophoblast cells. In human cytotrophoblast and trophoblast-derived choriocarcinoma cells, janus kinase signalling is blocked by protein tyrosine phosphatases (PTPs), whereas in mouse trophoblast, histone deacetylases (HDACs) inhibit IRG expression. Here, we used genome-wide transcriptional profiling to investigate the collective roles of PTPs and HDACs on regulation of IRG expression in human choriocarcinoma cells. Logic-rules were optimized to derive regulatory modes governing gene expression patterns observed upon different combinations of treatment with PTP and HDAC inhibitors. The results demonstrate that IRGs can be divided into several categories in human choriocarcinoma cells, each of which is subject to distinct mechanisms of repression. Hence, the regulatory modes identified in this study suggest that human trophoblast and choriocarcinoma cells may evade the potentially deleterious consequences of exposure to IFN-γ by using several overlapping mechanisms to block IRG expression.

Association of Dynamic Changes in the CD4 T-Cell Transcriptome With Disease Severity During Primary Respiratory Syncytial Virus Infection in Young Infants

“…To assess T-cell transcription factor activity, we interpreted CD4 gene expression patterns associated with severity using Bayesian estimation of transcription factor activity [22,23]. To assess T-cell transcription factor activity, we interpreted CD4 gene expression patterns associated with severity using Bayesian estimation of transcription factor activity [22,23].…”

Executable pathway analysis using ensemble discrete-state modeling for large-scale data

“…BONITA’s excellent performance on simulated data and in modeling pathway modulation calls for verifying its performance in similar experimental setting. RNA-seq data from our previous study investigating Interferon-regulated genes (IRG) following stimulation of human choriocarcinoma (Jar) cells with IFN- γ with or without pervanadate, a protein tyrosine phosphatase inhibitor, or valproic acid, a histone deacetylase (HDAC) inhibitor [23] was used. Human choriocarcinoma cells are hypo-responsive to IFN- γ stimulation due to impaired activation of the JAK-STAT pathway [30, 31].…”

“…We previously showed modulation of certain IRGs by inhibitor alone. Nonetheless, stimulation with both IFN- γ and inhibitors did not reveal elicitation of higher number of pathways using existing tools such as CAMERA in [23]. In this study, BONITA, CAMERA, and CLIPPER were used to assess significance of 37 immune pathways in IFN- γ treatment with or without inhibitors compared to untreated cells (Fig 6, S1 Table).…”

“…Comparison of BONITA pathway analysis with CLIPPER and CAMERA was performed using previously published RNA-sequencing data measuring IFN- γ signaling modulation in human choriocarcinoma cells [23] and a study representing translational design where peripheral blood mononuclear cells from infants with mild or severe respiratory syncitial virus were assessed by RNA-sequencing [22]. Data was processed using voom [24] for CAMERA or CLIPPER.…”

A systems genomics approach uncovers molecular associates of RSV severity

“…These weights were then used in the transcription factor analyses. Conserved binding sites from JASPER across hg19, mm10 and rn6 were identified from as described previously 37 . A hypergeometric test was performed to identify enriched binding sites 38,39 .…”