Core transcriptional regulatory circuits in prion diseases

Taek-Kyun Kim,Brenda Canine,Nathan D Price,Ji-Hoon Cho,Daehee Hwang,Inyoul Lee,George Carlson,Leroy Hood,Andrew Keller

doi:10.1186/s13041-020-0551-3

Abstract

Complex diseases involve dynamic perturbations of pathophysiological processes during disease progression. Transcriptional programs underlying such perturbations are unknown in many diseases. Here, we present core transcriptional regulatory circuits underlying early and late perturbations in prion disease. We first identified cellular processes perturbed early and late using time-course gene expression data from three prion-infected mouse strains. We then built a transcriptional regulatory network (TRN) describing regulation of early and late processes. We found over-represented feed-forward loops (FFLs) comprising transcription factor (TF) pairs and target genes in the TRN. Using gene expression data of brain cell types, we further selected active FFLs where TF pairs and target genes were expressed in the same cell type and showed correlated temporal expression changes in the brain. We finally determined core transcriptional regulatory circuits by combining these active FFLs. These circuits provide insights into transcriptional programs for early and late pathophysiological processes in prion disease.

Highlights

Living organisms execute diverse cellular processes by operation of biological networks [1]
Dynamic perturbations of cellular processes associated with prion diseases Previously, we proposed core genes associated with pathogenesis of prion disease that showed shared dynamic changes in differential expression along progression of prion disease [2]
Prion diseases induce early and late expression changes of hundreds of genes, leading to alteration of cellular processes associated with PrPSc accumulation, microglial/astrocytic activation, synaptic degeneration, Fig. 5 Core transcriptional regulatory circuits (TRCs) in microglia and oligodendrocyte precursor cells (OPCs) and characteristics of TRCs

Summary

Introduction

Living organisms execute diverse cellular processes by operation of biological networks [1]. Such operation of the networks is perturbed under pathological conditions, involving changes of nodes in their abundances and/or edges in their activities. These changes result in dynamic perturbations of pathophysiological processes during the course of disease progression [2]. Expression changes of TFs and Transmissible PrP-prion disease, which is caused by misfolding, aggregation, and spread of misfolded forms of prion protein (PrPSc), is an excellent model system to study dynamic perturbations of pathophysiological processes during disease progression since disease initiation is defined by inoculation. Neurodegenerative diseases involving PrP are designated as PrP-prion diseases that can be transmitted experimentally as are the mouse prions used in this study, or

Methods

Results

Conclusion