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  Aligning Single-Cell Developmental and Reprogramming Trajectories Identifies Molecular Determinants of Myogenic Reprogramming Outcome

Cacchiarelli, D., Qiu, X., Srivatsan, S., Manfredi, A., Ziller, M., Overbey, E., et al. (2018). Aligning Single-Cell Developmental and Reprogramming Trajectories Identifies Molecular Determinants of Myogenic Reprogramming Outcome. Cell Systems, 7(3): e3, pp. 258-268. doi:10.1016/j.cels.2018.07.006.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-4CB5-C Version Permalink: http://hdl.handle.net/21.11116/0000-0003-4CB6-B
Genre: Journal Article

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 Creators:
Cacchiarelli, Davide , Author
Qiu, Xiaojie , Author
Srivatsan, Sanjay , Author
Manfredi, Anna , Author
Ziller, Michael , Author
Overbey, Eliah , Author
Grimaldi, Antonio , Author
Grimsby, Jonna , Author
Pokharel, Prapti , Author
Livak, Kenneth J. , Author
Li, Shuqiang, Author
Meissner, Alexander1, 2, 3, Author              
Mikkelsen, Tarjei S. , Author
Rinn, John L. , Author
Trapnell, Cole , Author
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2The Broad Institute of MIT and Harvard, Cambridge, MA, USA, ou_persistent22              
3Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA, ou_persistent22              

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Free keywords: pseudotime; reprogramming; single-cell genomics
 Abstract: Cellular reprogramming through manipulation of defined factors holds great promise for large-scale production of cell types needed for use in therapy and for revealing principles of gene regulation. However, most reprogramming systems are inefficient, converting only a fraction of cells to the desired state. Here, we analyze MYOD-mediated reprogramming of human fibroblasts to myotubes, a well-characterized model system for direct conversion by defined factors, at pseudotemporal resolution using single-cell RNA-seq. To expose barriers to efficient conversion, we introduce a novel analytic technique, trajectory alignment, which enables quantitative comparison of gene expression kinetics across two biological processes. Reprogrammed cells navigate a trajectory with branch points that correspond to two alternative decision points, with cells that select incorrect branches terminating at aberrant or incomplete reprogramming outcomes. Analysis of these branch points revealed insulin and BMP signaling as crucial molecular determinants of reprogramming. Single-cell trajectory alignment enables rigorous quantitative comparisons between biological trajectories found in diverse processes in development, reprogramming, and other contexts.

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Language(s): eng - English
 Dates: 2018-07-232018-09-052018-09-26
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.cels.2018.07.006
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Title: Cell Systems
Source Genre: Journal
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Publ. Info: Maryland Heights, MO : Elsevier
Pages: 11 Volume / Issue: 7 (3) Sequence Number: e3 Start / End Page: 258 - 268 Identifier: ISSN: 2405-4720
CoNE: https://pure.mpg.de/cone/journals/resource/2405-4720