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3 Publications

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    12/01/19 | High-throughput dense reconstruction of cell lineages.
    Isabel Espinosa Medina , Garcia-Marques J, Cepko C, Lee T
    Open Biology. 2019 Dec 01;9(12):190229. doi: 10.1098/rsob.190229

    The first meeting exclusively dedicated to the 'High-throughput dense reconstruction of cell lineages' took place at Janelia Research Campus (Howard Hughes Medical Institute) from 14 to 18 April 2019. Organized by Tzumin Lee, Connie Cepko, Jorge Garcia-Marques and Isabel Espinosa-Medina, this meeting echoed the recent eruption of new tools that allow the reconstruction of lineages based on the phylogenetic analysis of DNA mutations induced during development. Combined with single-cell RNA sequencing, these tools promise to solve the lineage of complex model organisms at single-cell resolution. Here, we compile the conference consensus on the technological and computational challenges emerging from the use of the new strategies, as well as potential solutions.

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    10/23/19 | Unlimited genetic switches for cell-type-specific manipulation.
    Garcia-Marques J, Yang C, Isabel Espinosa Medina , Mok K, Koyama M, Lee T
    Neuron. 2019 Oct 23;104(2):227-38. doi: https://doi.org/10.1016/j.neuron.2019.07.005

    Gaining independent genetic access to discrete cell types is critical to interrogate their biological functions as well as to deliver precise gene therapy. Transcriptomics has allowed us to profile cell populations with extraordinary precision, revealing that cell types are typically defined by a unique combination of genetic markers. Given the lack of adequate tools to target cell types based on multiple markers, most cell types remain inaccessible to genetic manipulation. Here we present CaSSA, a platform to create unlimited genetic switches based on CRISPR/Cas9 (Ca) and the DNA repair mechanism known as single-strand annealing (SSA). CaSSA allows engineering of independent genetic switches, each responding to a specific gRNA. Expressing multiple gRNAs in specific patterns enables multiplex cell-type-specific manipulations and combinatorial genetic targeting. CaSSA is a new genetic tool that conceptually works as an unlimited number of recombinases and will facilitate genetic access to cell types in diverse organisms.

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    05/30/19 | CLADES: a programmable sequence of reporters for lineage analysis
    Garcia-Marques J, Yang C, Isabel Espinosa Medina , Koyama M, Lee T
    bioRxiv. 2019 May 30:. doi: https://doi.org/10.1101/655308

    We present CLADES (Cell Lineage Access Driven by an Edition Sequence), a technology for cell lineage studies based on CRISPR/Cas9. CLADES relies on a system of genetic switches to activate and inactivate reporter genes in a pre-determined order. Targeting CLADES to progenitor cells allows the progeny to inherit a sequential cascade of reporters, coupling birth order with reporter expression. This gives us temporal resolution of lineage development that can be used to deconstruct an extended cell lineage by tracking the reporters expressed in the progeny. When targeted to the germ line, the same cascade progresses across animal generations, marking each generation with the corresponding combination of reporters. CLADES thus offers an innovative strategy for making programmable cascades of genes that can be used for genetic manipulation or to record serial biological events.

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