A Generalized Gene-Regulatory Network Model of Stem Cell Differentiation for Predicting Lineage Specifiers
نویسندگان
چکیده
Identification of cell-fate determinants for directing stem cell differentiation remains a challenge. Moreover, little is known about how cell-fate determinants are regulated in functionally important subnetworks in large gene-regulatory networks (i.e., GRN motifs). Here we propose a model of stem cell differentiation in which cell-fate determinants work synergistically to determine different cellular identities, and reside in a class of GRN motifs known as feedback loops. Based on this model, we develop a computational method that can systematically predict cell-fate determinants and their GRN motifs. The method was able to recapitulate experimentally validated cell-fate determinants, and validation of two predicted cell-fate determinants confirmed that overexpression of ESR1 and RUNX2 in mouse neural stem cells induces neuronal and astrocyte differentiation, respectively. Thus, the presented GRN-based model of stem cell differentiation and computational method can guide differentiation experiments in stem cell research and regenerative medicine.
منابع مشابه
A computational strategy for predicting lineage specifiers in stem cell subpopulations.
Stem cell differentiation is a complex biological event. Our understanding of this process is partly hampered by the co-existence of different cell subpopulations within a given population, which are characterized by different gene expression states driven by different underlying transcriptional regulatory networks (TRNs). Such cellular heterogeneity has been recently explored with the modern s...
متن کاملPromoter Methylation and Gene Expression in Human CD34+ Stem Cells Derived Erythroid Lineage by MicroRNA
Background: Stem Cell differentiation is a process composed of vast variety of factors which are controlled by a network of certain mechanisms. This study aims to determine the possible role of DNA methylation, a potent regulator of VHL, ECAD and RUNX3 genes during Erythroid differentiation driven by miR-451. Materials and Methods: To determine the methylation status of promoters and the e...
متن کاملNuclear Architecture and Epigenetics of Lineage Choice
Differentiation is an epigenetic process which is installed by changes of transcriptional programs over successive cellular divisions. A number of studies have reported the effects of biochemical modifications of chromatin (DNA and chromatin proteins) on the regulation of transcription. Although, these studies are able to explain how transcription of a given gene is regulated (toward activation...
متن کاملLineage Specifiers: New Players in the Induction of Pluripotency
Pluripotency-associated factors and their rivals, lineage specifiers, have long been considered the determining factors for the identity of pluripotent and differentiated cells, respectively. Therefore, factors that are employed for cellular reprogramming in order to induce pluripotency have been identified mainly from embryonic stem cell (ESC)-enriched and pluripotency-associated factors. Rece...
متن کاملKey Regulatory Gene Expression in Erythroleukemia Differentiation
The characteristics of cellular and molecular mechanisms associated with cell proliferation and differentiation is important to understand malignancy. In this report we characterise a leukemic model, D5A1, to study the action of differentiation agent, cellular events and gene expression of the selected transcription factors. Cells induced with 4 mM hexamethylene bisacetamide (HMBA) caused signs...
متن کامل