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    • In the current study we used only gene expression

    2018-10-20

    In the current study, we used only gene expression data for the analysis; however, phosphoproteomics data could also be used to assign weights to the signaling interactome for the inference of niche determinants. An important limitation of the method is that it considers only DERs as the sources of niche induced signaling to regulate the expression of downstream TFs for a given phenotype. Nevertheless, even those receptors that are not differentially expressed can play a crucial role in regulating the target TFs for the stable maintenance of TRNs. Nevertheless, given only gene expression data with limited number of replicates, it is not feasible to quantitate absolute expression levels of genes without resorting to differential gene expression. However, with the advancements in single cell sequencing techniques, that can offer expression levels at single cell resolution, one can more reliably quantitate absolute gene expression levels for a given cell type. In such cases, our method does not need to rely on differential gene expression and can take advantage of absolute expression status of the receptors to infer the niche determinants. Further, this could allow considering multiple phenotypes simultaneously without the need for pair-wise comparison. Therefore, the proposed method is flexible in its application to different kinds of data including phosphoproteomics and single cell RNA sequencing.
    Materials and methods A schematic representation of our method is shown in Fig. 1 and the detailed description of the methods is provided in the Supplementary Information.
    Acknowledgements
    Introduction Remarkable progress has been made in the research and application of neural stem apexbio calculator (NSCs) and progenitor cells (NPCs) demonstrating their tremendous potential for stem-cell based cell therapy or targeting endogenous NPCs to treat CNS injury and neurodegenerative diseases (Gage and Temple, 2013; Goldman et al., 2012; Gupta et al., 2012; Lu et al., 2012; Ming and Song, 2011). New opportunities have emerged to discover neural regenerative therapeutics towards significant unmet medical needs. However, many challenges still remain. For example, in injured CNS and under disease conditions, transplanted NPCs preferentially become astrocytes (Aboody et al., 2011; Reekmans et al., 2012; Robel et al., 2011). Small molecules that modulate the developmental processes of NSCs or NPCs towards desired cell fate not only offer significant opportunities for therapeutic drugs targeting endogenous NPCs for repair and regeneration, but also could enhance the efficacy of NSC transplantation for neuronal replacement (Li et al., 2013). Once committed to a certain cell fate, NPCs undergo cell cycle arrest and terminal differentiation leading to the exhibition of cell-type-specific features. NPC differentiation including neurogenesis and gliogenesis is a highly orchestrated process that is tightly regulated via both extrinsic environmental signals and intrinsic changes in gene expression and epigenetic regulation. Several crucial signaling pathways including Wnt, Notch and the bone morphogenetic proteins (BMPs) pathway have been identified in regulating the development of NPCs (Faigle and Song, 2013; Kriegstein and Alvarez-Buylla, 2009). The interplay of transcription factors and epigenetic modifiers, including histone modifications, DNA methylation and microRNAs during development is essential for NPCs to control self-renewal, fate specification, and differentiation (Hirabayashi and Gotoh, 2010; Juliandi et al., 2010). Suppression of astrocytic lineage genes during the neurogenic phase is one of the key cell-intrinsic epigenetic mechanisms underlying fate specification (Kanski et al., 2014; Sun et al., 2001). Recent studies have identified many different types of epigenetic regulators, including polycomb group and trithorax group proteins, DNA-damage inducible protein 45b, methyl-CpG-binding protein MBD1, DNA methyltransferases, histone deacetylases (HDACs) and acetyltransferases (HATs), which are involved in the tight regulation of the proliferation and specification of NPCs or the differentiation and maturation of newborn neurons (Lim et al., 2009; Ma et al., 2010; Wu et al., 2010; Zhao et al., 2003). In the case of histone modifications, extensive studies have now illustrated the important role of the histone code in methylation and acetylation, epigenetic writers ( HATs) and erasers (HDACs) in neurogenesis (Hsieh et al., 2004; Merson et al., 2006; Montgomery et al., 2009; Prozorovski et al., 2008; Yu et al., 2009). However, little is known about epigenetic readers in the development of NPCs and neurogenesis.