In silico identification of transcriptional mediators responsible for adipocyte de-differentiation in humans.

• Grant number: 25/09845-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2025
• End date: June 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Carlos Henrique Grossi Sponton
• Grantee: Maria Luísa Soares Leite
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 19/15025-5 - Unveiling the PRDM16 transcriptional complex related to the inhibition of ceramides synthesis genes in adipocytes, AP.JP

Abstract

Gene perturbation experiments (deletion or overexpression) are the best approach to study gene function. However, systematic perturbation experiments involving a large number of genes are generally prohibitive due to experimental limitations and ethical concerns. The application of single-cell technologies in gene perturbation experiments allows for the determination of a gene's functionality and, consequently, the definition of a cellular phenotype. Experimental methods capable of inducing perturbation of specific genes in target cells are described in the literature, but they present high operational costs and technical challenges. The use of computational methods for determining gene regulatory networks (GRNs) represents an effective and low-cost way to assess the function of genes of interest. GRN-based approaches are promising because they reconstruct systematic gene associations from unperturbed single-cell data. In this context, a recently developed method (CellOracle) integrates multimodal data to build customized GRN models specifically designed to simulate changes in cell identity following the perturbation of transcription factors (TFs). This method provides a systematic and intuitive interpretation of the context-dependent role of TFs in regulating cell identity. Thus, the aim of this project is to use the computational method CellOracle to identify transcriptional mediators responsible for the mechanism of de-differentiation. To achieve this, in silico perturbation analyses (deletion and overexpression) of TFs will be performed using publicly available single-cell data from human white adipocytes. (AU)