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Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons

View ORCID ProfileIshwariya Venkatesh, Vatsal Mehra, Zimei Wang, Ben Califf, Murray G. Blackmore
doi: https://doi.org/10.1101/259408
Ishwariya Venkatesh
aDepartment of Biomedical Sciences, Marquette University, 53201
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Vatsal Mehra
aDepartment of Biomedical Sciences, Marquette University, 53201
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Zimei Wang
aDepartment of Biomedical Sciences, Marquette University, 53201
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Ben Califf
aDepartment of Biomedical Sciences, Marquette University, 53201
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Murray G. Blackmore
aDepartment of Biomedical Sciences, Marquette University, 53201
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ABSTRACT

Axon regeneration in the central nervous system is prevented in part by a developmental decline in the intrinsic regenerative ability of maturing neurons. This loss of axon growth ability likely reflects widespread changes in gene expression, but the mechanisms that drive this shift remain unclear. Chromatin accessibility has emerged as a key regulatory mechanism in other cellular contexts, raising the possibility that chromatin structure may contribute to the age-dependent loss of regenerative potential. Here we establish an integrated bioinformatic pipeline that combines analysis of developmentally dynamic gene networks with transcription factor regulation and genome-wide maps of chromatin accessibility. When applied to the developing cortex, this pipeline detected overall closure of chromatin in sub-networks of genes associated with axon growth. We next analyzed mature CNS neurons that were supplied with various pro-regenerative transcription factors. Unlike prior results with SOX11 and KLF7, here we found that neither JUN nor an activated form of STAT3 promoted substantial corticospinal tract regeneration. Correspondingly, chromatin accessibility in JUN or STAT3 target genes was substantially lower than in predicted targets of SOX11 and KLF7. Finally, we used the pipeline to predict pioneer factors that could potentially relieve chromatin constraints at growth-associated loci. Overall this integrated analysis substantiates the hypothesis that dynamic chromatin accessibility contributes to the developmental decline in axon growth ability and influences the efficacy of pro-regenerative interventions in the adult, while also pointing toward selected pioneer factors as high-priority candidates for future combinatorial experiments.

Acknowledgments

This work was supported by grants from NINDS, the International Spinal Research Trust, the Bryon Riesch Paralysis Foundation and The Craig Nielsen Foundation. The authors declare no competing financial interests. The authors acknowledge ENCODE consortia and The Bing Ren lab at UCSD that generated the ATAC-seq datasets used in this study.

Footnotes

  • Conflict of Interest: None

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 03, 2018.
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Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons
Ishwariya Venkatesh, Vatsal Mehra, Zimei Wang, Ben Califf, Murray G. Blackmore
bioRxiv 259408; doi: https://doi.org/10.1101/259408
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Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons
Ishwariya Venkatesh, Vatsal Mehra, Zimei Wang, Ben Califf, Murray G. Blackmore
bioRxiv 259408; doi: https://doi.org/10.1101/259408

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