title: Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity.
abstract: Efficient transcriptional programming promises to open new frontiers in regenerative medicine. However, mechanisms by which programming factors transform cell fate are unknown, preventing more rational selection of factors to generate desirable cell types. Three transcription factors, Ngn2, Isl1 and Lhx3, were sufficient to program rapidly and efficiently spinal motor neuron identity when expressed in differentiating mouse embryonic stem cells. Replacement of Lhx3 by Phox2a led to specification of cranial, rather than spinal, motor neurons. Chromatin immunoprecipitation-sequencing analysis of Isl1, Lhx3 and Phox2a binding sites revealed that the two cell fates were programmed by the recruitment of Isl1-Lhx3 and Isl1-Phox2a complexes to distinct genomic locations characterized by a unique grammar of homeodomain binding motifs. Our findings suggest that synergistic interactions among transcription factors determine the specificity of their recruitment to cell type-specific binding sites and illustrate how a single transcription factor can be repurposed to program different cell types.
authors.affiliation: Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia University Medical Center, New York, New York, USA. eom204@nyu.edu
authors.forename: Esteban O
authors.initials: EO
authors.lastname: Mazzoni
authors.forename: Shaun
authors.initials: S
authors.lastname: Mahony
authors.forename: Michael
authors.initials: M
authors.lastname: Closser
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Morrison
authors.forename: Stephane
authors.initials: S
authors.lastname: Nedelec
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Williams
authors.forename: Disi
authors.initials: D
authors.lastname: An
authors.forename: David K
authors.initials: DK
authors.lastname: Gifford
authors.forename: Hynek
authors.initials: H
authors.lastname: Wichterle
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells; D015870:Gene Expression; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D009046:Motor Neurons / Q000166:cytology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017434:Protein Structure, Tertiary; D013116:Spinal Cord / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D014157:Transcription Factors; C094898:Lhx3 protein; C102938:Neurog2 protein, mouse; C512773:Olig2 protein, mouse; C491060:Phox2a protein, mouse; C063843:insulin gene enhancer binding protein Isl-1