Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration

Abstract

Injured peripheral sensory neurons switch to a regenerative state after axon injury, which requires transcriptional and epigenetic changes. However, the roles and mechanisms of gene inactivation after injury are poorly understood. Here, we show that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. Ubiquitin-like containing PHD ring finger 1 (UHRF1), a critical epigenetic regulator involved in DNA methylation, increases upon axon injury and is required for robust axon regeneration. The increased level of UHRF1 results from a decrease in miR-9. The level of another target of miR-9, the transcriptional regulator RE1 silencing transcription factor (REST), transiently increases after injury and is required for axon regeneration. Mechanistically, UHRF1 interacts with DNA methyltransferases (DNMTs) and H3K9me3 at the promoter region to repress the expression of the tumor suppressor gene phosphatase and tensin homolog (PTEN) and REST. Our study reveals an epigenetic mechanism that silences tumor suppressor genes and restricts REST expression in time after injury to promote axon regeneration.

Satellite glial cells promote regenerative growth in sensory neurons

“…For in vitro regeneration assay, dorsal root ganglia were isolated from time pregnant e13.5 CD-1 mice and cultured as previously described (Cho et al, 2013;Oh et al, 2018). Briefly, after a short centrifugation, dissection media was aspirated and cells were digested in .05% Trypsin-EDTA for 25 minutes in 37 o C. Next, cells were pelleted by centrifuging for 2 minutes at 500 x g, the supernatant was aspirated, and Neurobasal was added.…”

News about the Role of the Transcription Factor REST in Neurons: From Physiology to Pathology

“…REST is a repressive transcription factor markedly reduced, by a considerable increase in its turnover, during the development of stem and progenitor cells. Its direct effects, taking place mostly by epigenetic mechanisms [14][15][16], involve the interaction with various modifiers, including small molecules, which affect the REST binding to chromatin remodelers as well as the ensuing nuclear reprogramming [1][2][3]17]. In addition to numerous, directly stimulated neuronal genes, low REST participates in the control of distinct regulatory factors, involved in the expression/repression of many other genes.…”

“…However, the subsequent activation of epigenetic DNA methylations rapidly results in the inhibition of REST together with its miRNA, miR-9. A consequence of the last processes is intense stimulation of axonal growth [15].…”

Peripheral nerve injury and myelination: Potential therapeutic strategies

“…The ever‐evolving field of epigenetics also has the potential to play an important role in peripheral nerve recovery and myelination (Arthur‐Farraj et al, ; Oh et al, ; Pereira et al, ; Salzer, ). Myelination by Schwann cells is under strict transcriptional control (Jagalur et al, ; Svaren & Meijer, ) involving sequential, feedforward cascades of promyelinating transcription factors where Sox 10 (SRY‐related HMG‐box‐10) and Oct6 (octamer‐binding transcription factor‐6) synergistically induce the expression of Krox20 (also termed early growth response gene: Egr2).…”

“…Therefore, future studies exploring the effects of different variables, such as wavelengths, dose, continuous or pulsed mode, application site, and type of radiation would verify the usefulness of LLLT in TPNI as an adjunct therapy. The ever-evolving field of epigenetics also has the potential to play an important role in peripheral nerve recovery and myelination (Arthur-Farraj et al, 2017;Oh et al, 2018;Pereira et al, 2012;Salzer, 2015). Myelination by Schwann cells is under strict transcriptional control (Jagalur et al, 2011;Svaren & Meijer, 2008) involving sequential, feedforward cascades of promyelinating transcription factors where Sox 10 (SRY-related HMG-box-10) and Oct6 (octamerbinding transcription factor-6) synergistically induce the expression of Krox20 (also termed early growth response gene: Egr2).…”