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Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades Underlying Adult Neurogenesis

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Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades Underlying Adult Neurogenesis Resource Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis Graphical Abstract Authors Jaehoon Shin, Daniel A. Berg, Yunhua Zhu, ..., Kimberly M. Christian, Guo-li Ming, Hongjun Song Correspondence [email protected] In Brief In vivo molecular dynamics of adult stem cells have been elusive. Shin et al. used single-cell RNA-seq and a novel bioinformatic approach named Waterfall to reconstruct somatic stem cell dynamics with unprecedented temporal resolution. The genome-wide molecular transitions they identified suggest commonalities among different somatic stem cell systems. Highlights Accession Numbers d Single-cell transcriptomes from adult NSCs form a GSE71485 continuous linear trajectory d Waterfall pipeline quantifies gene expression over continuous biological processes d Adult NSC-specific metabolic pathways and active niche signal integration capacity d Augmented translation capacity is the first hallmark of adult NSC activation Shin et al., 2015, Cell Stem Cell 17, 360–372 September 3, 2015 ª2015 Elsevier Inc. http://dx.doi.org/10.1016/j.stem.2015.07.013 Cell Stem Cell Resource Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis Jaehoon Shin,1,2 Daniel A. Berg,2,3,7 Yunhua Zhu,2,3 Joseph Y. Shin,4 Juan Song,2,3 Michael A. Bonaguidi,2,3 Grigori Enikolopov,8,9 David W. Nauen,5 Kimberly M. Christian,2,3 Guo-li Ming,1,2,3,4,6 and Hongjun Song1,2,3,4,* 1Graduate Program in Cellular and Molecular Medicine 2Institute for Cell Engineering 3Department of Neurology 4The Solomon Snyder Department of Neuroscience 5Department of Pathology 6Department of Psychiatry and Behavioral Sciences Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 7Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17 117 Stockholm, Sweden 8Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA 9Center for Developmental Genetics and Department of Anesthesiology, Stony Brook University, Stony Brook, NY 11794, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2015.07.013 SUMMARY brain disorders. Mechanistic analysis of stem cell biology re- quires comprehensive quantification of molecular properties, Somatic stem cells contribute to tissue ontogenesis, such as gene expression. In contrast to traditional approaches homeostasis, and regeneration through sequential targeting individual candidate genes, transcriptome profiling processes. Systematic molecular analysis of stem through RNA-sequencing (RNA-seq) provides an unbiased and cell behavior is challenging because classic ap- quantitative proxy for molecular features of cellular states. proaches cannot resolve cellular heterogeneity or Such a blueprint may reveal unexpected features of NSC capture developmental dynamics. Here we provide a biology, generate hypotheses for functional analysis, and lead to novel strategies to manipulate neurogenesis processes. comprehensive resource of single-cell transcriptomes Classic approaches for molecular characterization of somatic of adult hippocampal quiescent neural stem cells stem cell behavior use population-based readouts at a few time (qNSCs) and their immediate progeny. We further points along development, which faces two major challenges: developed Waterfall, a bioinformatic pipeline, to sta- resolving cellular heterogeneity and capturing developmental tistically quantify singe-cell gene expression along a dynamics. Adult stem cells constitute a minor population within de novo reconstructed continuous developmental tra- complex tissues, intermingled with their progeny at different jectory. Our study reveals molecular signatures of developmental stages and supporting cells. They switch among adult qNSCs, characterized by active niche signaling different states, such as quiescence and activation (Li and integration and low protein translation capacity. Our Clevers, 2010), and thus exhibit significant cellular and molecular analyses further delineate molecular cascades under- differences even upon prospective isolation via fluorescence- lying qNSC activation and neurogenesis initiation, activated cell sorting or genetic labeling (Codega et al., 2014; Lu et al., 2011). Furthermore, snapshots of molecular composi- exemplified by decreased extrinsic signaling capac- tion at selected time points are not sufficient to elucidate the ity, primed translational machinery, and regulatory dynamic nature of stem cell development. switches in transcription factors, metabolism, and en- Single-cell RNA-seq generates gene expression profiles at the ergy sources. Our study reveals the molecular contin- resolution of an individual cell and has thus far revealed uum underlying adult neurogenesis and illustrates molecular profiles of cell types that were not previously recog- how Waterfall can be used for single-cell omics ana- nized at the population level (Stegle et al., 2015). Single-cell lyses of various continuous biological processes. RNA-seq has not yet been widely adopted for adult somatic stem cell studies due to technical difficulties in obtaining individ- ual stem cells from complex tissues. Further, the stochastic na- INTRODUCTION ture of gene expression in individual cells (Muramoto et al., 2012; Novick and Weiner, 1957; Raj et al., 2006) may lead to overesti- In discrete regions of the adult mammalian brain, quiescent mation of cellular heterogeneity and requires a new approach for neural stem cells (qNSCs) continuously generate new neurons statistical quantification. And for biological systems with only a through a recurrent process involving quiescent to active state few known markers, current approaches are not sufficient to transitions, cell-cycle entry, and neuronal fate specification map out a developmental trajectory at high resolution from sin- (Ming and Song, 2011). Understanding molecular mechanisms gle-cell datasets (Bendall et al., 2014; Trapnell et al., 2014). underlying adult NSC regulation and neurogenesis will advance Despite recent advances in acquiring snapshots of tran- our knowledge of neural development and plasticity and enable scriptomes, epigenomes, and proteomes from individual cells, new approaches for regenerative medicine and treatment of a remaining hurdle is the lack of methodology to identify 360 Cell Stem Cell 17, 360–372, September 3, 2015 ª2015 Elsevier Inc. A B CFP+ single cells CFP– single cells 014421~3 28 Day: Serially diluted RNA from wild-type dentate gyrus Cell cycle ) 4 3 100 10 2 1 Quiescent Activated (TPM, log scale) 0 NSC NSC eIPC Nes::CFP 1 MN CFP expression Blbp Tbr2 Dcx level (TPM, x10 NB IN Sox2 Sox11 qNSC 0 IPC Individual single-cells sorted Gfap Pcna by CFP transcript level C bulk RNA CFP– CFP+ Actb GapdhUbb Blbp/Fabp7Gfap Sox2 Sox11 Tbr2/Eomes Gstm1 Figure 1. Single-Cell Transcriptomes of Adult Neural Stem Cells and Their Immediate Progeny (A) A schematic diagram of the process of adult neurogenesis in the dentate gyrus of the mouse hippocampus. Once quiescent neural stem cells (qNSCs) become activated (aNSCs), they enter the cell cycle and generate early intermediate progenitor cells (eIPCs), which in turn give rise to neuroblasts (NB), immature neurons (IN), and then mature neurons (MN). Area highlighted with blue background indicates cell types fluorescently labeled in adult Nestin-CFPnuc animals. (B) Expression levels of transcript encoding CFP in each single-cell and diluted whole-dentate RNA samples (TPM, transcripts per million). Inset: enlarged view of CFP transcript levels in logarithmic scale of samples with low abundance of CFP transcript. (C) Representative coverage profile of diluted total RNA from the whole dentate gyrus, CFP– individual cells, and CFP+ individual cells at selected genomic loci, including house-keeping genes (b-Actin/Actb, Gapdh, and Ubiquitin B/Ubb), known NSC markers (Blbp/Fabp7, Gfap, and Sox2), known IPC markers (Sox11 and Tbr2/Eomes), and a potential new NPC marker (Gstm1). See also Figure S1. molecular state transitions over a developmental continuum. used a transgenic mouse line that expresses nucleus-localized Cells are destroyed during acquisition of omic data, so the CFP under the Nestin regulatory elements (Nes-CFPnuc)(Encinas same cell can’t be tracked over time. Here we developed a et al., 2006), in which CFP proteins carry over from adult conceptually different approach, analogous to the ‘‘shot-gun’’ qNSCs to their immediate progeny (collectively named NPCs; method used in the human genome project characterized Figure S1A). The SMART-seq protocol (Ramsko¨ ld et al., 2012) by parallel sequencing and bioinformatic reconstruction. We was modified by the addition of a DNase I treatment step to focused on the narrow time window of adult qNSC activation remove genomic DNA for single-cell cDNA amplification (Fig- and neurogenesis initiation. Using the Nestin-CFPnuc transgenic ure S1A). In total, we performed single-cell RNA-seq for 142 genetic labeling system, we produced single-cell transcriptomes CFPnuc+ and 26 CFPnuc– single cells (Table S1). Total RNA from from a mixed population of precursor cells at different develop- wild-type adult mouse dentate gyri was serially diluted to 3 pg mental stages. We then developed a bioinformatic pipeline and processed in parallel for comparison. named Waterfall to reconstruct continuous biological processes We achieved, on average, 87% mapping onto annotated at single-cell resolution using adult neurogenesis as our model, genes (Table S1). Sequencing reads were evenly
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