Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity
Author(s)Mazzoni, Esteban O.; Mahony, Shaun; Closser, Michael; Morrison, Carolyn A.; Nedelec, Stephane; Williams, Damian J; An, Disi; Wichterle, Hynek; Gifford, David K.; ... Show more Show less
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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.
DepartmentMassachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Nature Publishing Group
Mazzoni, Esteban O, Shaun Mahony, Michael Closser, Carolyn A Morrison, Stephane Nedelec, Damian J Williams, Disi An, David K Gifford, and Hynek Wichterle. “Synergistic Binding of Transcription Factors to Cell-Specific Enhancers Programs Motor Neuron Identity.” Nat Neurosci 16, no. 9 (July 21, 2013): 1219–1227.
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