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

Silvia Velasco, Mahmoud M. Ibrahim, Akshay Kakumanu, Görkem Garipler, Begüm Aydin, Mohamed Ahmed Al-Sayegh, Antje Hirsekorn, Farah Abdul-Rahman, Rahul Satija, Uwe Ohler, Shaun Mahony, Esteban O. Mazzoni

Research output: Contribution to journalArticle

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)205-217.e8
JournalCell Stem Cell
Volume20
Issue number2
DOIs
StatePublished - Feb 2 2017

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology

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    Velasco, S., Ibrahim, M. M., Kakumanu, A., Garipler, G., Aydin, B., Al-Sayegh, M. A., Hirsekorn, A., Abdul-Rahman, F., Satija, R., Ohler, U., Mahony, S., & Mazzoni, E. O. (2017). A Multi-step Transcriptional and Chromatin State Cascade Underlies Motor Neuron Programming from Embryonic Stem Cells. Cell Stem Cell, 20(2), 205-217.e8. https://doi.org/10.1016/j.stem.2016.11.006