title: PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system.
abstract: Axonal regenerative failure is a major cause of neurological impairment following central nervous system (CNS) but not peripheral nervous system (PNS) injury. Notably, PNS injury triggers a coordinated regenerative gene expression programme. However, the molecular link between retrograde signalling and the regulation of this gene expression programme that leads to the differential regenerative capacity remains elusive. Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. Thus, we find a specific epigenetic mechanism that regulates axonal regeneration of CNS axons, suggesting novel targets for clinical application.
authors.affiliation: 1] Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany [2].
authors.forename: Radhika
authors.initials: R
authors.lastname: Puttagunta
authors.affiliation: 1] Department of Axonal Growth and Regeneration, German Center for Neurodegenerative Disease, 53175 Bonn, Germany [2].
authors.forename: Andrea
authors.initials: A
authors.lastname: Tedeschi
authors.affiliation: 1] Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany [2] Graduate School for Cellular and Molecular Neuroscience, University of Tu¨bingen, 72076 Tu¨bingen, Germany.
authors.forename: Marilia Grando
authors.initials: MG
authors.lastname: Sória
authors.affiliation: 1] Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany [2] Division of Brain Sciences, Department of Medicine, Imperial College London, Hammersmith Campus, London W12 ONN, UK.
authors.forename: Arnau
authors.initials: A
authors.lastname: Hervera
authors.affiliation: 1] Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany [2] Graduate School for Cellular and Molecular Neuroscience, University of Tu¨bingen, 72076 Tu¨bingen, Germany.
authors.forename: Ricco
authors.initials: R
authors.lastname: Lindner
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Khizr I
authors.initials: KI
authors.lastname: Rathore
authors.affiliation: 1] Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany [2] Graduate School for Cellular and Molecular Neuroscience, University of Tu¨bingen, 72076 Tu¨bingen, Germany.
authors.forename: Perrine
authors.initials: P
authors.lastname: Gaub
authors.affiliation: 1] Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany [2] Graduate School for Cellular and Molecular Neuroscience, University of Tu¨bingen, 72076 Tu¨bingen, Germany [3] DZNE, German Center for Neurodegenerative Diseases, D-72076 Tu¨bingen, Germany.
authors.forename: Yashashree
authors.initials: Y
authors.lastname: Joshi
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Tuan
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Schmandke
authors.affiliation: Department of Axonal Growth and Regeneration, German Center for Neurodegenerative Disease, 53175 Bonn, Germany.
authors.forename: Claudia J
authors.initials: CJ
authors.lastname: Laskowski
authors.affiliation: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Université de Strasbourg-CNRS, GDR CNRS, Strasbourg 67000, France.
authors.forename: Anne-Laurence
authors.initials: AL
authors.lastname: Boutillier
authors.affiliation: Department of Axonal Growth and Regeneration, German Center for Neurodegenerative Disease, 53175 Bonn, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bradke
authors.affiliation: 1] Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany [2] Division of Brain Sciences, Department of Medicine, Imperial College London, Hammersmith Campus, London W12 ONN, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Di Giovanni
mesh_terms: D000107:Acetylation; D000818:Animals; D001369:Axons / Q000201:enzymology*; D002490:Central Nervous System / Q000502:physiology*; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009416:Nerve Regeneration; D013119:Spinal Cord Injuries / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D006657:Histones; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor