scholarly journals The developmental hourglass model is applicable to the spinal cord based on single‐cell transcriptomes and non‐conserved cis ‐regulatory elements

2021 ◽  
Author(s):  
Katsuki Mukaigasa ◽  
Chie Sakuma ◽  
Hiroyuki Yaginuma
Keyword(s):  
Spinal Cord ◽  
Single Cell ◽  
Regulatory Elements ◽  
Hourglass Model ◽  
Developmental Hourglass

scholarly journals The developmental hourglass model is applicable to the spinal cord

2021 ◽  
Author(s):  
Katsuki Mukaigasa ◽  
Chie Sakuma ◽  
Hiroyuki Yaginuma
Keyword(s):  
Spinal Cord ◽  
Regulatory Elements ◽  
Spinal Neurons ◽  
Upstream Gene ◽  
Spinal Cord Development ◽  
Neuronal Progenitor ◽  
Before And After ◽  
Hourglass Model ◽  
Fate Determinants ◽  
Developmental Hourglass

SummaryThe developmental hourglass model predict that embryonic morphology is most conserved at mid-embryonic stage and diverge at early and late stage. This model is generally considered by whole embryonic level. Here, we demonstrate that the hourglass model is also applicable to the more reduced element, the spinal cord. In the middle of the spinal cord development, dorsoventrally arrayed neuronal progenitor domains are established, which is conserved among vertebrates. We found that, by comparing the single-cell transcriptomes between mice and zebrafish, V3 interneurons, a subpopulation of the post-mitotic spinal neurons, display the divergent molecular profiles. We also found non-conservation of cis-regulatory elements located around the progenitor fate determinants, indicating the rewiring of the upstream gene regulatory network. These results demonstrate that, despite the conservation of the progenitor domains, processes before and after the progenitor domain specification has diverged. This study may help understand the molecular basis of the developmental hourglass model.

scholarly journals Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons

2021 ◽  
Vol 24 (4) ◽  
pp. 572-583 ◽  
Author(s):  
Jacob A. Blum ◽  
Sandy Klemm ◽  
Jennifer L. Shadrach ◽  
Kevin A. Guttenplan ◽  
Lisa Nakayama ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Single Cell ◽  
Motor Neurons ◽  
Molecular Diversity ◽  
Adult Mouse ◽  
Transcriptomic Analysis ◽  
Mouse Spinal Cord

scholarly journals Comprehensive analysis of single cell ATAC-seq data with SnapATAC

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Rongxin Fang ◽  
Sebastian Preissl ◽  
Yang Li ◽  
Xiaomeng Hou ◽  
Jacinta Lucero ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Cell Analysis ◽  
Expression Patterns ◽  
Regulatory Elements ◽  
Cellular Heterogeneity ◽  
Specific Gene ◽  
Open Chromatin ◽  
Cell Type ◽  
Process Data ◽  
Cell Type Specific

AbstractIdentification of the cis-regulatory elements controlling cell-type specific gene expression patterns is essential for understanding the origin of cellular diversity. Conventional assays to map regulatory elements via open chromatin analysis of primary tissues is hindered by sample heterogeneity. Single cell analysis of accessible chromatin (scATAC-seq) can overcome this limitation. However, the high-level noise of each single cell profile and the large volume of data pose unique computational challenges. Here, we introduce SnapATAC, a software package for analyzing scATAC-seq datasets. SnapATAC dissects cellular heterogeneity in an unbiased manner and map the trajectories of cellular states. Using the Nyström method, SnapATAC can process data from up to a million cells. Furthermore, SnapATAC incorporates existing tools into a comprehensive package for analyzing single cell ATAC-seq dataset. As demonstration of its utility, SnapATAC is applied to 55,592 single-nucleus ATAC-seq profiles from the mouse secondary motor cortex. The analysis reveals ~370,000 candidate regulatory elements in 31 distinct cell populations in this brain region and inferred candidate cell-type specific transcriptional regulators.

scholarly journals Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

2022 ◽  
Vol 8 ◽  
Author(s):  
Eric Schoger ◽  
Sara Lelek ◽  
Daniela Panáková ◽  
Laura Cecilia Zelarayán
Keyword(s):  
Gene Expression ◽  
Precision Medicine ◽  
Single Cell ◽  
Regulatory Networks ◽  
Transcriptional Control ◽  
Regulatory Elements ◽  
Comprehensive Overview ◽  
Endogenous Gene ◽  
Cell Technologies ◽  
Organ Systems

Molecular and genetic differences between individual cells within tissues underlie cellular heterogeneities defining organ physiology and function in homeostasis as well as in disease states. Transcriptional control of endogenous gene expression has been intensively studied for decades. Thanks to a fast-developing field of single cell genomics, we are facing an unprecedented leap in information available pertaining organ biology offering a comprehensive overview. The single-cell technologies that arose aided in resolving the precise cellular composition of many organ systems in the past years. Importantly, when applied to diseased tissues, the novel approaches have been immensely improving our understanding of the underlying pathophysiology of common human diseases. With this information, precise prediction of regulatory elements controlling gene expression upon perturbations in a given cell type or a specific context will be realistic. Simultaneously, the technological advances in CRISPR-mediated regulation of gene transcription as well as their application in the context of epigenome modulation, have opened up novel avenues for targeted therapy and personalized medicine. Here, we discuss the fast-paced advancements during the recent years and the applications thereof in the context of cardiac biology and common cardiac disease. The combination of single cell technologies and the deep knowledge of fundamental biology of the diseased heart together with the CRISPR-mediated modulation of gene regulatory networks will be instrumental in tailoring the right strategies for personalized and precision medicine in the near future. In this review, we provide a brief overview of how single cell transcriptomics has advanced our knowledge and paved the way for emerging CRISPR/Cas9-technologies in clinical applications in cardiac biomedicine.

scholarly journals Single-cell Sequencing Reveals Brain/Spinal Cord Oligodendrocyte Precursor Heterogeneity and Requirement for mTOR in Cholesterol Biosynthesis and Myelin Maintenance

2020 ◽  
Author(s):  
Luipa Khandker ◽  
Marisa A. Jeffries ◽  
Yun-Juan Chang ◽  
Marie L. Mather ◽  
Jennifer N. Bourne ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Single Cell ◽  
Single Cell Analysis ◽  
Cholesterol Biosynthesis ◽  
Adult Brain ◽  
Cell Analysis ◽  
Sequencing Studies ◽  
Oligodendrocyte Precursor ◽  
Brain And Spinal Cord ◽  
The Brain

AbstractBrain and spinal cord oligodendroglia have distinct functional characteristics, and cell autonomous loss of individual genes can result in different regional phenotypes. However, sequencing studies to date have not revealed distinctions between brain and spinal cord oligodendroglia. Using single-cell analysis of oligodendroglia during myelination, we demonstrate that brain and spinal cord precursors are transcriptionally distinct, defined predominantly by cholesterol biosynthesis. We further identify mechanistic target of rapamycin (mTOR) as a major regulator promoting cholesterol biosynthesis in oligodendroglia. Oligodendroglial-specific loss of mTOR compromises cholesterol biosynthesis in both the brain and spinal cord. Importantly, mTOR loss has a greater impact on cholesterol biosynthesis in spinal cord oligodendroglia that corresponds with more pronounced developmental deficits. However, loss of mTOR in brain oligodendroglia ultimately results in oligodendrocyte death, spontaneous demyelination, and impaired axonal function, demonstrating that mTOR is required for myelin maintenance in the adult brain.

scholarly journals Selection against expression noise explains the origin of the hourglass pattern of Evo-Devo

2019 ◽  
Author(s):  
Jialin Liu ◽  
Michael Frochaux ◽  
Vincent Gardeux ◽  
Bart Deplancke ◽  
Marc Robinson-Rechavi
Keyword(s):  
Regulatory Elements ◽  
Mutational Robustness ◽  
Expression Variability ◽  
Expression Noise ◽  
Environmental Perturbations ◽  
Phylotypic Stage ◽  
Robustness To Noise ◽  
Selection For ◽  
Hourglass Model ◽  
Evo Devo

The evolution of embryological development has long been characterized by deep conservation. Both morphological and transcriptomic surveys have proposed a “hourglass” model of Evo-Devo1,2. A stage in mid-embryonic development, the phylotypic stage, is highly conserved among species within the same phylum3–7. However, the reason for this phylotypic stage is still elusive. Here we hypothesize that the phylotypic stage might be characterized by selection for robustness to noise and environmental perturbations. This could lead to mutational robustness, thus evolutionary conservation of expression and the hourglass pattern. To test this, we quantified expression variability of single embryo transcriptomes throughout fly Drosophila melanogaster embryogenesis. We found that indeed expression variability is lower at extended germband, the phylotypic stage. We explain this pattern by stronger histone modification mediated transcriptional noise control at this stage. In addition, we find evidence that histone modifications can also contribute to mutational robustness in regulatory elements. Thus, the robustness to noise does indeed contributes to robustness of gene expression to genetic variations, and to the conserved phylotypic stage.

scholarly journals Haplotype-aware single-cell multiomics uncovers functional effects of somatic structural variation

2021 ◽  
Author(s):  
Hyobin Jeong ◽  
Karen Grimes ◽  
Peter-Martin Bruch ◽  
Tobias Rausch ◽  
Patrick Hasenfeld ◽  
...  
Keyword(s):  
Single Cell ◽  
Nucleosome Occupancy ◽  
Single Cells ◽  
Chromosomal Rearrangements ◽  
Regulatory Elements ◽  
Computational Method ◽  
Tumour Heterogeneity ◽  
Cancer Genomes ◽  
Functional Consequences ◽  
Oncogenic Transcription Factor

Somatic structural variants (SVs) are widespread in cancer genomes, however, their impact on tumorigenesis and intra-tumour heterogeneity is incompletely understood, since methods to functionally characterize the broad spectrum of SVs arising in cancerous single-cells are lacking. We present a computational method, scNOVA, that couples SV discovery with nucleosome occupancy analysis by haplotype-resolved single-cell sequencing, to systematically uncover SV effects on cis-regulatory elements and gene activity. Application to leukemias and cell lines uncovered SV outcomes at several loci, including dysregulated cancer-related pathways and mono-allelic oncogene expression near SV breakpoints. At the intra-patient level, we identified different yet overlapping subclonal SVs that converge on aberrant Wnt signaling. We also deconvoluted the effects of catastrophic chromosomal rearrangements resulting in oncogenic transcription factor dysregulation. scNOVA directly links SVs to their functional consequences, opening the door for single-cell multiomics of SVs in heterogeneous cell populations.

scholarly journals Single cell transcriptome profiling of the human developing spinal cord reveals a conserved genetic programme with human specific features

2021 ◽  
Author(s):  
Teresa Rayon ◽  
Rory J. Maizels ◽  
Christopher Barrington ◽  
James Briscoe
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Single Cell ◽  
Motor Neurons ◽  
Neural Tube ◽  
Transcriptome Profiling ◽  
Cell Types ◽  
Human Embryos ◽  
Neuronal Populations ◽  
Cell Transcriptome

AbstractThe spinal cord receives input from peripheral sensory neurons and controls motor output by regulating muscle innervating motor neurons. These functions are carried out by neural circuits comprising molecularly and physiologically distinct neuronal subtypes that are generated in a characteristic spatial-temporal arrangement from progenitors in the embryonic neural tube. The systematic mapping of gene expression in mouse embryos has provided insight into the diversity and complexity of cells in the neural tube. For human embryos, however, less information has been available. To address this, we used single cell mRNA sequencing to profile cervical and thoracic regions in four human embryos of Carnegie Stages (CS) CS12, CS14, CS17 and CS19 from Gestational Weeks (W) 4-7. In total we recovered the transcriptomes of 71,219 cells. Analysis of progenitor and neuronal populations from the neural tube, as well as cells of the peripheral nervous system, in dorsal root ganglia adjacent to the neural tube, identified dozens of distinct cell types and facilitated the reconstruction of the differentiation pathways of specific neuronal subtypes. Comparison with existing mouse datasets revealed the overall similarity of mouse and human neural tube development while highlighting specific features that differed between species. These data provide a catalogue of gene expression and cell type identity in the developing neural tube that will support future studies of sensory and motor control systems and can be explored at https://shiny.crick.ac.uk/scviewer/neuraltube/.

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