PT  - JOURNAL ARTICLE
AU  - Ishwariya Venkatesh
AU  - Vatsal Mehra
AU  - Zimei Wang
AU  - Matthew T. Simpson
AU  - Erik Eastwood
AU  - Advaita Chakraborty
AU  - Zac Beine
AU  - Derek Gross
AU  - Michael Cabahug
AU  - Greta Olson
AU  - Murray G. Blackmore
TI  - Co-occupancy analysis reveals novel transcriptional synergies for axon growth
AID  - 10.1101/2020.06.12.146159
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.06.12.146159
4099  - http://biorxiv.org/content/early/2021/03/03/2020.06.12.146159.short
4100  - http://biorxiv.org/content/early/2021/03/03/2020.06.12.146159.full
AB  - 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 novel bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that potentiate the effects of pro-regenerative Klf6. High content screens of neurite outgrowth identified cooperative activity by 12 candidates, and systematic testing in an animal 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 novel TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics roadmap to detect TF synergy.Competing Interest StatementThe authors have declared no competing interest.