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A multi-step transcriptional and chromatin state cascade underlies motor neuron programming from embryonic stem cells

Official URL:https://doi.org/10.1016/j.stem.2016.11.006
PubMed:View item in PubMed
Creators Name:Velasco, S. and Ibrahim, M.M. and Kakumanu, A. and Garipler, G. and Aydin, B. and Al-Sayegh, M.A. and Hirsekorn, A. and Abdul-Rahman, F. and Satija, R. and Ohler, U. and Mahony, S. and Mazzoni, E.O.
Journal Title:Cell Stem Cell
Journal Abbreviation:Cell Stem Cell
Volume:20
Number:2
Page Range:205-217
Date:2 February 2017
Keywords:Biological Models, Cellular Reprogramming, Chromatin, DNA, Embryonic Stem Cells, Genetic Enhancer Elements, Genetic Loci, Genetic Promoter Regions, Genetic Transcription, Motor Neurons, Nucleotide Motifs, Protein Binding, RNA Sequence Analysis, Single-Cell Analysis, Time Factors, Transcription Factors, Animals, Mice
Abstract:Direct cell programming via overexpression of transcription factors (TFs) aims to control cell fate with the degree of precision needed for clinical applications. However, the regulatory steps involved in successful terminal cell fate programming remain obscure. We have investigated the underlying mechanisms by looking at gene expression, chromatin states, and TF binding during the uniquely efficient Ngn2, Isl1, and Lhx3 motor neuron programming pathway. Our analysis reveals a highly dynamic process in which Ngn2 and the Isl1/Lhx3 pair initially engage distinct regulatory regions. Subsequently, Isl1/Lhx3 binding shifts from one set of targets to another, controlling regulatory region activity and gene expression as cell differentiation progresses. Binding of Isl1/Lhx3 to later motor neuron enhancers depends on the Ebf and Onecut TFs, which are induced by Ngn2 during the programming process. Thus, motor neuron programming is the product of two initially independent transcriptional modules that converge with a feedforward transcriptional logic.
ISSN:1934-5909
Publisher:Cell Press (U.S.A.)
Item Type:Article

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