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1. CRISPR–Cas9 epigenome editing enables high-throughput screening for functional regulatory elements in the human genome.
Large genome-mapping consortia and thousands of genome-wide association studies have identified non-protein-coding elements in the genome as having a central role in various biological processes. However, decoding the functions of the millions of putative regulatory elements discovered in these studies remains challenging. CRISPR–Cas9-based epigenome editing technologies have enabled precise perturbation of the activity of specific regulatory elements. Here Tyler S Klann at Duke University in Durham, North Carolina, USA and his colleagues describe CRISPR–Cas9-based epigenomic regulatory element screening (CERES) for improved high-throughput screening of regulatory element activity in the native genomic context. Using dCas9KRAB repressor and dCas9p300 activator constructs and lentiviral single guide RNA libraries to target DNase I hypersensitive sites surrounding a gene of interest, they carried out both loss- and gain-of-function screens to identify regulatory elements for the β-globin and HER2 loci in human cells. CERES readily identified known and previously unidentified regulatory elements, some of which were dependent on cell type or direction of perturbation. This technology allows the high-throughput functional annotation of putative regulatory elements in their native chromosomal context, the authors suggest.
Read more, please click http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3853.html
2. A living mesoscopic cellular automaton made of skin scales.
In vertebrates, skin colour patterns emerge from nonlinear dynamical microscopic systems of cell interactions. Here Liana Manukyan at University of Geneva in Geneva, Switzerland and his colleagues show that in ocellated lizards a quasi-hexagonal lattice of skin scales, rather than individual chromatophore cells, establishes a green and black labyrinthine pattern of skin colour. They analysed time series of lizard scale colour dynamics over four years of their development and demonstrate that this pattern is produced by a cellular automaton (a grid of elements whose states are iterated according to a set of rules based on the states of neighbouring elements) that dynamically computes the colour states of individual mesoscopic skin scales to produce the corresponding macroscopic colour pattern. Using numerical simulations and mathematical derivation, they identify how a discrete von Neumann cellular automaton emerges from a continuous Turing reaction–diffusion system. Skin thickness variation generated by three-dimensional morphogenesis of skin scales causes the underlying reaction–diffusion dynamics to separate into microscopic and mesoscopic spatial scales, the latter generating a cellular automaton. Their study indicates that cellular automata are not merely abstract computational systems, but can directly correspond to processes generated by biological evolution.
Read more, please click http://www.nature.com/nature/journal/v544/n7649/full/nature22031.html
3. Virus genomes reveal factors that spread and sustained the Ebola epidemic.
The 2013–2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here Gytis Dudas at University of Edinburgh in Edinburgh, UK and his colleagues reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. They test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic ‘gravity’ model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. They address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, they reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics.
Read more, please click http://www.nature.com/nature/journal/v544/n7650/full/nature22040.html
4. Structure and allosteric inhibition of excitatory amino acid transporter 1.
Human members of the solute carrier 1 (SLC1) family of transporters take up excitatory neurotransmitters in the brain and amino acids in peripheral organs. Dysregulation of the function of SLC1 transporters is associated with neurodegenerative disorders and cancer. Here Juan C. Canul-Tec at Institut Pasteur in Paris, France and his colleagues present crystal structures of a thermostabilized human SLC1 transporter, the excitatory amino acid transporter 1 (EAAT1), with and without allosteric and competitive inhibitors bound. The structures reveal architectural features of the human transporters, such as intra- and extracellular domains that have potential roles in transport function, regulation by lipids and post-translational modifications. The coordination of the allosteric inhibitor in the structures and the change in the transporter dynamics measured by hydrogen–deuterium exchange mass spectrometry reveal a mechanism of inhibition, in which the transporter is locked in the outward-facing states of the transport cycle. Their results provide insights into the molecular mechanisms underlying the function and pharmacology of human SLC1 transporters.
Read more, please click http://www.nature.com/nature/journal/vaop/ncurrent/full/nature22064.html
5. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model.
Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here Pia Rivetti di Val Cervo at Karolinska Institutet in Stockholm, Sweden and his colleagues describe an alternative strategy for Parkinson’s disease in which dopamine neurons are generated by direct conversion of astrocytes. Using three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218, collectively designated NeAL218, they reprogram human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons (iDANs). Reprogramming efficiency in vitro is improved by small molecules that promote chromatin remodeling and activate the TGFβ, Shh and Wnt signaling pathways. The reprogramming efficiency of human astrocytes reaches up to 16%, resulting in iDANs with appropriate midbrain markers and excitability. In a mouse model of Parkinson’s disease, NeAL218 alone reprograms adult striatal astrocytes into iDANs that are excitable and correct some aspects of motor behavior in vivo, including gait impairments. With further optimization, this approach may enable clinical therapies for Parkinson’s disease by delivery of genes rather than cells.
Read more, please click http://www.nature.com/nbt/journal/vaop/ncurrent/full/nbt.3835.html