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Cell Stem Cell. 2017 Feb 2;20(2):205-217.e8. doi: 10.1016/j.stem.2016.11.006. Epub 2016 Dec 8.

A Multi-step Transcriptional and Chromatin State Cascade Underlies Motor Neuron Programming from Embryonic Stem Cells.

Author information

1
Department of Biology, New York University, 100 Washington Square East, New York, NY 10003, USA.
2
Department of Biology, Humboldt Universität zu Berlin, Unter den Linden 6, Berlin 10117, Germany.
3
Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany.
4
Center for Eukaryotic Gene Regulation, Department of Biochemistry & Molecular Biology, Penn State University, Pennsylvania, USA.
5
Division of Science and Math, New York University, Abu-Dhabi, UAE.
6
New York Genome Center, New York University, New York, USA.
#
Contributed equally

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.

KEYWORDS:

direct programming; motor neuron; neuron

PMID:
27939218
PMCID:
PMC5291817
DOI:
10.1016/j.stem.2016.11.006
[Indexed for MEDLINE]
Free PMC Article

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