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Deciphering Master Gene Regulators and Associated Networks of Human Mesenchymal Stromal Cells

Published version
Peer-reviewed

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Authors

Sánchez-Luis 
Joaquín-García 
Campos-Laborie 
Sánchez-Guijo 
Rivas 

Abstract

Mesenchymal Stromal Cells (MSC) are multipotent cells characterized by self-renewal, multilineage differentiation, and immunomodulatory properties. To obtain a gene regulatory profile of human MSCs, we generated a compendium of more than two hundred cell samples with genome-wide expression data, including a homogeneous set of 93 samples of five related primary cell types: bone marrow mesenchymal stem cells (BM-MSC), hematopoietic stem cells (HSC), lymphocytes (LYM), fibroblasts (FIB), and osteoblasts (OSTB). All these samples were integrated to generate a regulatory gene network using the algorithm ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks; based on mutual information), that finds regulons (groups of target genes regulated by transcription factors) and regulators (i.e., transcription factors, TFs). Furtherly, the algorithm VIPER (Algorithm for Virtual Inference of Protein-activity by Enriched Regulon analysis) was used to inference protein activity and to identify the most significant TF regulators, which control the expression profile of the studied cells. Applying these algorithms, a footprint of candidate master regulators of BM-MSCs was defined, including the genes EPAS1, NFE2L1, SNAI2, STAB2, TEAD1, and TULP3, that presented consistent upregulation and hypomethylation in BM-MSCs. These TFs regulate the activation of the genes in the bone marrow MSC lineage and are involved in development, morphogenesis, cell differentiation, regulation of cell adhesion, and cell structure.

Description

Keywords

mesenchymal stromal cells, transcription factor, regulons, master regulators, gene networks, transcriptomics, bioinformatic, meta-analysis

Journal Title

Biomolecules

Conference Name

Journal ISSN

2218-273X

Volume Title

10

Publisher

MDPI
Sponsorship
Instituto de Salud Carlos III (PI18/00591)
Horizon 2020 Framework Programme (737390)