A gene regulatory architecture that controls region‐independent dynamics of oligodendrocyte differentiation

Abstract

Oligodendrocytes (OLs) facilitate information processing in the vertebrate central nervous system via axonal ensheathment. The structure and dynamics of the regulatory network that mediates oligodendrogenesis are poorly understood. We employed bioinformatics and meta-analysis of highthroughput datasets to reconstruct a regulatory network underpinning OL differentiation. From this network, we identified families of feedforward loops comprising the transcription factors (TFs) Olig2, Sox10, and Tcf7l2 and their targets. Among the targets, we found eight other TFs related to OL differentiation, suggesting a hierarchical architecture in which some TFs (Olig2, Sox10, and Tcf7l2) regulate via feedforward loops the expression of others (Sox2, Sox6, Sox11, Nkx2-2, Nkx6-2, Hes5, Myt1, and Myrf ). Model simulations with a kinetic model reproduced the mechanisms of OL differentiation only when in the model, Sox10-mediated repression of Tcf7l2 by miR-338/miR-155 was introduced, a prediction confirmed in genetic functional experiments. Additional model simulations suggested that OLs from dorsal regions emerge through BMP/Sox9 signaling. K E Y W O R D S network biology, ODE mathematical model, Oligodendrocytes, TF-miRNA circuits, TFregulated feedforward loop 1 | INTRODUCTION Rapid information processing in the vertebrate central nervous system (CNS) is dependent on saltatory conduction as a consequence of axonal ensheathment by myelin-producing glial cells (Nave & Werner, 2014).Developmental disturbances in myelin production (i.e., dysmyelination) or impairment of myelin sheaths (i.e., demyelination) are typical hallmarks of neurodegenerative diseases in humans including leukodystrophies and Multiple Sclerosis. Oligodendrocytes (OLs) are the myelin-forming glial cells of the CNS that originate from embryonic neuroepithelial stem cells located at the ventricular zone of the developing spinal cord. OLs are generated from OL precursor cells (OPCs) that are derived from these germinal zones, undergoing a number of developmental stages followed by terminal differentiation and initiation of myelin production (Rowitch, 2004).Myelination is a complex process and requires appropriate coordination and organization of downstream gene regulatory and metabolic processes. For example, genes encoding for myelin proteins are already expressed in the progenitor stages during development, followed by their protein synthesis during OL maturation, and the Abbreviations: FPKM, fragment per kilobase of exon per million fragments

Neural Differentiation Dynamics Controlled by Multiple Feedback Loops in a Comprehensive Molecular Interaction Network

“…Therefore, OLIG2 regulation might involve a delay mechanism to elongate the period and a mechanism to amplify dispersion. Recently, a similar method was used to analyze oligodendrocyte differentiation [52]. Similar to our study, the authors used a manual method to construct a network; however, they also introduced publicly available interaction data from omics databases.…”

“…In comparison with our method, this approach may reduce the number of false-negative interactions. On the other hand, the study [52] only focused on two-to four-node feedback loops. Our contraction method may detect a larger regulatory system of oligodendrocyte differentiation.…”

The Progress in Diagnosis and Treatment of Exosomes and MicroRNAs on Epileptic Comorbidity Depression

“…So the exosomes secreted by MSCs have the effect of resistance to demyelination. Besides, myelination is a complex process which is regulated by micro RNAs, such as miR-219 and miR-338 (71,72). Milbreta et al applied a scaffolding system which enables sustained non-viral delivery of microRNAs to oligodendrocytes, and they found that the animals treated with miR-219/miR-338 preserved a higher number of Olig2, than the control group (73).…”

A systems pharmacology approach to determine the mechanisms of action of pleiotropic natural products in breast cancer from transcriptome data

“…Nowadays, concurrent integration of experimentally-derived omics data with a priori interaction data is a common approach in systems biology to obtain context-specific subnetworks 9 . To this end, a number of computational tools have been proposed by different groups to map and construct subnetworks from transcriptome data 10 and applied to several diseases, including breast cancer 11 , hepatocellular carcinoma 12, 13 , liver fibrosis 14 and neurodegenerative diseases 15 .…”