Abstract
The failure of axon regeneration in the CNS limits recovery from damage and disease. Members of the KLF family of transcription factors can exert both positive and negative effects on axon regeneration, but the underlying mechanisms are unclear. Here we show that forced expression of KLF6 promotes axon regeneration by corticospinal tract neurons in the injured spinal cord. RNA sequencing identified 454 genes whose expression changed upon forced KLF6 expression in vitro, including sub-networks that were highly enriched for functions relevant to axon extension including cytoskeleton remodeling, lipid synthesis, and bioenergetics. In addition, promoter analysis predicted a functional interaction between KLF6 and a second transcription factor, STAT3, and genome-wide footprinting using ATAC-Seq data confirmed frequent co-occupancy. Co-expression of the two factors yielded a synergistic elevation of neurite growth in vitro. These data clarify the transcriptional control of axon growth and point the way toward novel interventions to promote CNS regeneration.
Highlights
Promoting effective regenerative axon growth after central nervous system (CNS) injury remains a critical unmet goal in neuroscience research
Efforts to identify optimal combinations are hampered by limited understanding of the transcriptional mechanisms that underlie Transcription factors (TFs)-triggered growth
We identified KLF6 as an effective pro-regenerative TF, and integrated transcriptional profiling with recent advances in gene network analyses to identify KLF6-responsive gene modules. We leveraged these insights to identify STAT3 as a TF that functionally synergizes with KLF6 in promoting axon extension and identified co-occupancy of the two factors in regulatory DNA associated with specific pro-regenerative gene networks
Summary
Promoting effective regenerative axon growth after central nervous system (CNS) injury remains a critical unmet goal in neuroscience research. We used motif analysis of promoter sequences in KLF6-responsive genes, to identify candidate transcription factors that were predicted to co-regulate these genes. For STAT3, a known pro-regenerative transcription factor, was highly enriched in the promoter sequences of KLF6-responsive genes, suggesting potential functional interaction between these two factors. Using ATAC-sec footprinting analysis, we show high co-occupancy by KLF6 and STAT3 on regulatory DNA in regeneration-relevant gene networks, indicating co-binding as a likely mechanism for the observed synergy. These data demonstrate substantial growth promotion by KLF6 in CNS neurons, clarify the associated transcriptional changes, and demonstrate functional synergy with STAT3
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