title: Comprehensive mapping of 5-hydroxymethylcytosine epigenetic dynamics in axon regeneration.
abstract: In contrast to central nervous system neurons, dorsal root ganglia (DRG) neurons can switch to a regenerative state after peripheral axotomy. In a screen for chromatin regulators of the regenerative responses in this conditioning lesion paradigm, we identified Tet methylcytosine dioxygenase 3 (Tet3) as upregulated in DRG neurons, along with increased 5-hydroxymethylcytosine (5hmC). We generated genome-wide 5hmC maps in adult DRG, which revealed that peripheral and central axotomy (leading to no regenerative effect) triggered differential 5hmC changes that are associated with distinct signaling pathways. 5hmC was altered in a large set of regeneration-associated genes (RAGs), including well-known RAGs, such as Atf3, Bdnf, and Smad1, that regulate axon growth potential of DRG neurons, thus supporting its role for RAG regulation. Our analyses also predicted HIF-1, STAT, and IRF as potential transcription factors that may collaborate with Tet3 for 5hmC modifications. Intriguingly, central axotomy resulted in widespread 5hmC modifications that had little overlap with those of peripheral axotomy, thus potentially constituting a roadblock for regeneration. Our study revealed 5hmC dynamics as a previously unrecognized epigenetic mechanism underlying the divergent responses after axonal injury.
authors.affiliation: a Fishberg Department of Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Yong-Hwee Eddie
authors.initials: YE
authors.lastname: Loh
authors.affiliation: a Fishberg Department of Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Koemeter-Cox
authors.affiliation: a Fishberg Department of Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Mattéa J
authors.initials: MJ
authors.lastname: Finelli
authors.affiliation: a Fishberg Department of Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: a Fishberg Department of Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai , New York , NY , USA.|b Department of Neurosurgery , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Roland H
authors.initials: RH
authors.lastname: Friedel
authors.affiliation: a Fishberg Department of Neuroscience , Friedman Brain Institute, Icahn School of Medicine at Mount Sinai , New York , NY , USA.|b Department of Neurosurgery , Icahn School of Medicine at Mount Sinai , New York , NY , USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zou
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D009416:Nerve Regeneration / Q000235:genetics*; D000071446:Neuronal Outgrowth / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D019208:Brain-Derived Neurotrophic Factor; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine
keywords: 5hmC; DNA methylation; DRG; Tet; axon injury; axon regeneration; conditioning lesion; epigenetics; regeneration-associated genes (RAG)