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"Klein, M."
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Lineage tracing meets single-cell omics: opportunities and challenges
A fundamental goal of developmental and stem cell biology is to map the developmental history (ontogeny) of differentiated cell types. Recent advances in high-throughput single-cell sequencing technologies have enabled the construction of comprehensive transcriptional atlases of adult tissues and of developing embryos from measurements of up to millions of individual cells. Parallel advances in sequencing-based lineage-tracing methods now facilitate the mapping of clonal relationships onto these landscapes and enable detailed comparisons between molecular and mitotic histories. Here we review recent progress and challenges, as well as the opportunities that emerge when these two complementary representations of cellular history are synthesized into integrated models of cell differentiation.Understanding developmental trajectories has recently been enabled by progress in modern lineage-tracing methods that combine genetic lineage analysis with omics-based characterization of cell states (particularly transcriptomes). In this Review, Wagner and Klein discuss the conceptual underpinnings, experimental strategies and analytical considerations of these approaches, as well as the biological insights gained.
Journal Article
Lineage tracing on transcriptional landscapes links state to fate during differentiation
Biologists have long attempted to understand how stem and progenitor cells in regenerating and embryonic tissues differentiate into mature cell types. Through the use of recent technical advances to sequence the genes expressed in thousands of individual cells, differentiation mechanisms are being revealed. Weinreb et al. extended these methods to track clones of cells (cell families) across time. Their approach reveals differences in cellular gene expression as cells progress through hematopoiesis, which is the process of blood production. Using machine learning, they tested how well gene expression measurements account for the choices that cells make. This work reveals that a considerable gap still exists in understanding differentiation mechanisms, and future methods are needed to fully understand—and ultimately control—cell differentiation. Science , this issue p. eaaw3381 Single-cell barcoding allows the tracking of gene expression states over time as blood cells differentiate during hematopoiesis. A challenge in biology is to associate molecular differences among progenitor cells with their capacity to generate mature cell types. Here, we used expressed DNA barcodes to clonally trace transcriptomes over time and applied this to study fate determination in hematopoiesis. We identified states of primed fate potential and located them on a continuous transcriptional landscape. We identified two routes of monocyte differentiation that leave an imprint on mature cells. Analysis of sister cells also revealed cells to have intrinsic fate biases not detectable by single-cell RNA sequencing. Finally, we benchmarked computational methods of dynamic inference from single-cell snapshots, showing that fate choice occurs earlier than is detected by state-of the-art algorithms and that cells progress steadily through pseudotime with precise and consistent dynamics.
Journal Article
The emergence of transcriptional identity in somatosensory neurons
More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments
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. It is unclear how specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess the developmental progression of transcriptional maturation of each subtype of principal somatosensory neuron, we generated a transcriptomic atlas of cells traversing the primary somatosensory neuron lineage in mice. Here we show that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds. Single-cell transcriptomic analyses of sensory neurons from mutant mice lacking transcription factors suggest that these broad-to-restricted transcription factors coordinate subtype-specific gene expression programs in subtypes in which their expression is maintained. We also show that neuronal targets are involved in this process; disruption of the prototypic target-derived neurotrophic factor NGF leads to aberrant subtype-restricted patterns of transcription factor expression. Our findings support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptionally unspecialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors.
Neuronal targets mediate the emergence of somatosensory neuron subtypes by altering the expression of neuronal transcription factors.
Journal Article
Global biogeochemical cycle of vanadium
Synthesizing published data, we provide a quantitative summary of the global biogeochemical cycle of vanadium (V), including both human-derived and natural fluxes. Through mining of V ores (130 × 10⁹ g V/y) and extraction and combustion of fossil fuels (600 × 10⁹ g V/y), humans are the predominant force in the geochemical cycle of V at Earth’s surface. Human emissions of V to the atmosphere are now likely to exceed background emissions by as much as a factor of 1.7, and, presumably, we have altered the deposition of V from the atmosphere by a similar amount. Excessive V in air and water has potential, but poorly documented, consequences for human health. Much of the atmospheric flux probably derives from emissions from the combustion of fossil fuels, but the magnitude of this flux depends on the type of fuel, with relatively low emissions from coal and higher contributions from heavy crude oils, tar sands bitumen, and petroleum coke. Increasing interest in petroleum derived from unconventional deposits is likely to lead to greater emissions of V to the atmosphere in the near future. Our analysis further suggests that the flux of V in rivers has been incremented by about 15% from human activities. Overall, the budget of dissolved V in the oceans is remarkably well balanced—with about 40 × 10⁹ g V/y to 50 × 10⁹ g V/y inputs and outputs, and a mean residence time for dissolved V in seawater of about 130,000 y with respect to inputs from rivers.
Journal Article
تكييف مناهج الطفولة المبكرة للأطفال ذوي الحاجات الخاصة
يتميز هذا الكتاب بأنه مصدر شامل لمعلمي الطفولة المبكرة وذو لغة بسيطة ومفهومة وهو يلائم مدى واسع للقراء والباحثين عن طرق دعم نمو الاطفال ذوي الحاجات الخاصة الملتحقين في بدائل الدمج الشامل لتربية الطفولة المبكرة وأسرهم ويقدم هذا الكتاب للمربين دليلا علميا وفعالا لايجاد فرص لتعلم الطفل من أنشطة المنهاج والانشطة الروتنية اليومية حيث يركز على مبادئ الدمج ومركزية دور الاسرة في تعلم ونمو الطفل وبالتاكيد دور معلمي تربية الطفولة المبكرة والتربية الخاصة ويحتوي الكتاب على الجداول والاشكال التي تبرز مراحل النمو عند الأطفال وكيفية تنميته باقتراحات محددة ومباشرة وبأمثلة عملية من الممارسات اليومية في الصف والمنزل.
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Single-cell mapping of gene expression landscapes and lineage in the zebrafish embryo
As embryos develop, numerous cell types with distinct functions and morphologies arise from pluripotent cells. Three research groups have used single-cell RNA sequencing to analyze the transcriptional changes accompanying development of vertebrate embryos (see the Perspective by Harland). Wagner et al. sequenced the transcriptomes of more than 90,000 cells throughout zebrafish development to reveal how cells differentiate during axis patterning, germ layer formation, and early organogenesis. Farrell et al. profiled the transcriptomes of tens of thousands of embryonic cells and applied a computational approach to construct a branching tree describing the transcriptional trajectories that lead to 25 distinct zebrafish cell types. The branching tree revealed how cells change their gene expression as they become more and more specialized. Briggs et al. examined whole frog embryos, spanning zygotic genome activation through early organogenesis, to map cell states and differentiation across all cell lineages over time. These data and approaches pave the way for the comprehensive reconstruction of transcriptional trajectories during development. Science , this issue p. 981 , p. eaar3131 , p. eaar5780 ; see also p. 967 Single-cell RNA sequencing reveals cell type trajectories and cell lineage in the developing zebrafish embryo. High-throughput mapping of cellular differentiation hierarchies from single-cell data promises to empower systematic interrogations of vertebrate development and disease. Here we applied single-cell RNA sequencing to >92,000 cells from zebrafish embryos during the first day of development. Using a graph-based approach, we mapped a cell-state landscape that describes axis patterning, germ layer formation, and organogenesis. We tested how clonally related cells traverse this landscape by developing a transposon-based barcoding approach (TracerSeq) for reconstructing single-cell lineage histories. Clonally related cells were often restricted by the state landscape, including a case in which two independent lineages converge on similar fates. Cell fates remained restricted to this landscape in embryos lacking the chordin gene. We provide web-based resources for further analysis of the single-cell data.
Journal Article