Identification of an early cell fate regulator by detecting dynamics in transcriptional heterogeneity and co-regulation during astrocyte differentiation

• Published in: NPJ systems biology and applications 2019-05, Vol.5 (1), p.18, Article 18
• Main Authors: Ando, Tatsuya, Kato, Ryuji, Honda, Hiroyuki
• Format: Article
• Language: English
• Subjects: 631/532; 631/553/2393; 631/553/2707; 631/553/2712; Animals; ASCL1 protein; Astrocytes; Astrocytes - cytology; Astrocytes - metabolism; Bioinformatics; Biomedical and Life Sciences; Cell Differentiation - genetics; Cell fate; Computational Biology/Bioinformatics; Computer Appl. in Life Sciences; Databases, Genetic; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Developmental - genetics; Gene Regulatory Networks - genetics; Humans; Life Sciences; Mice; Molecular modelling; Neural stem cells; Neural Stem Cells - cytology; Neurogenesis; Single-Cell Analysis - methods; Stem cells; Systems Biology; Transcription
• ISSN: 2056-7189; 2056-7189
• DOI: 10.1038/s41540-019-0095-2

There are an increasing number of reports that characterize the temporal behavior of gene expression at the single-cell level during cell differentiation. Despite accumulation of data describing the heterogeneity of biological responses, the dynamics of gene expression heterogeneity and its regulation during the differentiation process have not been studied systematically. To understand transcriptional heterogeneity during astrocyte differentiation, we analyzed single-cell transcriptional data from cells representing the different stages of astrocyte differentiation. When we compared the transcriptional variability of co-expressed genes between the undifferentiated and differentiated states, we found that there was significant increase in transcriptional variability in the undifferentiated state. The genes showing large changes in both “variability” and “correlation” between neural stem cells (NSCs) and astrocytes were found to be functionally involved in astrocyte differentiation. We determined that these genes are potentially regulated by Ascl1 , a previously known oscillatory gene in NSCs. Pharmacological blockade of Ntsr2 , which is transcriptionally co-regulated with Ascl1 , showed that Ntsr2 may play an important role in the differentiation from NSCs to astrocytes. This study shows the importance of characterizing transcriptional heterogeneity and rearrangement of the co-regulation network between different cell states. It also highlights the potential for identifying novel regulators of cell differentiation that will further increase our understanding of the molecular mechanisms underlying the differentiation process. Computational neuroscience: transcriptional heterogeneity spotlights the key players in astrogenesis In addition to average gene expression levels across stem cell populations, the variation in gene expression between single cells triggered by biological oscillations can provide new insights. A team led by Hiroyuki Honda at Nagoya University in Japan introduced the concept of analyzing gene expression heterogeneity within a cell population to elucidate the mechanism of astrocyte differentiation. By scoring the variability and correlation within single-cell gene expression data, the expression heterogeneity in a cell population was found to increase before differentiation. The analysis highlighted key differentiation regulators like Ascl1, Sox9, and Ntsr2. This work underscores the importance of understanding transcriptional heterogenei