title: A Multi-step Transcriptional and Chromatin State Cascade Underlies Motor Neuron Programming from Embryonic Stem Cells.
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.
authors.affiliation: Department of Biology, New York University, 100 Washington Square East, New York, NY 10003, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Velasco
authors.affiliation: Department of Biology, Humboldt Universität zu Berlin, Unter den Linden 6, Berlin 10117, Germany.|Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Ibrahim
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry & Molecular Biology, Penn State University, Pennsylvania, USA.
authors.forename: Akshay
authors.initials: A
authors.lastname: Kakumanu
authors.affiliation: Department of Biology, New York University, 100 Washington Square East, New York, NY 10003, USA.
authors.forename: Görkem
authors.initials: G
authors.lastname: Garipler
authors.affiliation: Department of Biology, New York University, 100 Washington Square East, New York, NY 10003, USA.
authors.forename: Begüm
authors.initials: B
authors.lastname: Aydin
authors.affiliation: Department of Biology, New York University, 100 Washington Square East, New York, NY 10003, USA.|Division of Science and Math, New York University, Abu-Dhabi, UAE.
authors.forename: Mohamed Ahmed
authors.initials: MA
authors.lastname: Al-Sayegh
authors.affiliation: Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Hirsekorn
authors.affiliation: Department of Biology, New York University, 100 Washington Square East, New York, NY 10003, USA.
authors.forename: Farah
authors.initials: F
authors.lastname: Abdul-Rahman
authors.affiliation: New York Genome Center, New York University, New York, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Satija
authors.affiliation: Department of Biology, Humboldt Universität zu Berlin, Unter den Linden 6, Berlin 10117, Germany.|Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, Berlin 13125, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Ohler
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry & Molecular Biology, Penn State University, Pennsylvania, USA.
authors.forename: Shaun
authors.initials: S
authors.lastname: Mahony
authors.affiliation: Department of Biology, New York University, 100 Washington Square East, New York, NY 10003, USA.
authors.forename: Esteban O
authors.initials: EO
authors.lastname: Mazzoni
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D056426:Genetic Loci; D051379:Mice; D008954:Models, Biological; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D014157:Transcription Factors; D004247:DNA
keywords: direct programming; motor neuron; neuron