Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity

Esteban O. Mazzoni, Shaun Mahony, Michael Closser, Carolyn A. Morrison, Stephane Nedelec, Damian J. Williams, Disi An, David K. Gifford, Hynek Wichterle

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1219-1227
Number of pages9
JournalNature Neuroscience
Volume16
Issue number9
DOIs
StatePublished - Sep 2013

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Motor Neurons
Transcription Factors
Binding Sites
Regenerative Medicine
Chromatin Immunoprecipitation

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mazzoni, E. O., Mahony, S., Closser, M., Morrison, C. A., Nedelec, S., Williams, D. J., ... Wichterle, H. (2013). Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity. Nature Neuroscience, 16(9), 1219-1227. https://doi.org/10.1038/nn.3467

Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity. / Mazzoni, Esteban O.; Mahony, Shaun; Closser, Michael; Morrison, Carolyn A.; Nedelec, Stephane; Williams, Damian J.; An, Disi; Gifford, David K.; Wichterle, Hynek.

In: Nature Neuroscience, Vol. 16, No. 9, 09.2013, p. 1219-1227.

Research output: Contribution to journalArticle

Mazzoni, EO, Mahony, S, Closser, M, Morrison, CA, Nedelec, S, Williams, DJ, An, D, Gifford, DK & Wichterle, H 2013, 'Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity', Nature Neuroscience, vol. 16, no. 9, pp. 1219-1227. https://doi.org/10.1038/nn.3467
Mazzoni, Esteban O. ; Mahony, Shaun ; Closser, Michael ; Morrison, Carolyn A. ; Nedelec, Stephane ; Williams, Damian J. ; An, Disi ; Gifford, David K. ; Wichterle, Hynek. / Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity. In: Nature Neuroscience. 2013 ; Vol. 16, No. 9. pp. 1219-1227.
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