Abstract
Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Because TFs often depend on cooperative activity, a major challenge is to identify and deploy optimal sets. Here we developed a bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that potentiate the effects of pro-regenerative Klf6 in vitro. High content screens of neurite outgrowth identified cooperative activity by 12 candidates, and systematic testing in a mouse model of corticospinal tract (CST) damage substantiated three novel instances of pairwise cooperation. Combined Klf6 and Nr5a2 drove the strongest growth, and transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics approach to detect TF cooperation.
Highlights
Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease
During periods of developmental axon growth, regeneration-associated genes (RAGs) expression is supported by pro-growth transcription factors (TFs) that bind to relevant promoter and enhancer regions, to activate transcription[3,6]
We examined cortices in which corticospinal tract (CST) neurons were identified by retrograde labeling and again detected low levels of Glial Acidic Fibrillary Protein (GFAP), CD11B, and Transferase dUTP Nick End Labeling (TUNEL) reactivity (Supplementary Fig. 7e–h, i, j)
Summary
Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Combined Klf[6] and Nr5a2 drove the strongest growth, and transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics approach to detect TF cooperation. We have identified novel combinations of TFs that drive enhanced axon growth in mature CNS neurons and provide a generalized computational roadmap for the discovery of cooperative activity between TFs with potential application to a wide range of neural activities
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