An integrative method to predict signalling perturbations for cellular transitions.
Nucleic Acids Res
; 47(12): e72, 2019 07 09.
Article
en En
| MEDLINE
| ID: mdl-30949696
ABSTRACT
Induction of specific cellular transitions is of clinical importance, as it allows to revert disease cellular phenotype, or induce cellular reprogramming and differentiation for regenerative medicine. Signalling is a convenient way to accomplish such transitions without transfer of genetic material. Here we present the first general computational method that systematically predicts signalling molecules, whose perturbations induce desired cellular transitions. This probabilistic method integrates gene regulatory networks (GRNs) with manually-curated signalling pathways obtained from MetaCore from Clarivate Analytics, to model how signalling cues are received and processed in the GRN. The method was applied to 219 cellular transition examples, including cell type transitions, and overall correctly predicted experimentally validated signalling molecules, consistently outperforming other well-established approaches, such as differential gene expression and pathway enrichment analyses. Further, we validated our method predictions in the case of rat cirrhotic liver, and identified the activation of angiopoietins receptor Tie2 as a potential target for reverting the disease phenotype. Experimental results indicated that this perturbation induced desired changes in the gene expression of key TFs involved in fibrosis and angiogenesis. Importantly, this method only requires gene expression data of the initial and desired cell states, and therefore is suited for the discovery of signalling interventions for disease treatments and cellular therapies.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Perfilación de la Expresión Génica
/
Redes Reguladoras de Genes
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Nucleic Acids Res
Año:
2019
Tipo del documento:
Article
País de afiliación:
Luxemburgo