Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge

Abstract

The number of Schwann cells is fitted to axonal length in peripheral nerves. This relationship is lost when tumorigenic stimuli induce uncontrolled Schwann cell proliferation, generating tumours such us neurofibromas and schwannomas. Schwann cells also re-enter the cell cycle following nerve injury during the process of Wallerian degeneration. In both cases proliferation is finally arrested. We show that in neurofibroma, the induction of Jmjd3 (jumonji domain containing 3, histone lysine demethylase) removes trimethyl groups on lysine-27 of histone-H3 and epigenetically activates the Ink4a/Arf-locus, forcing Schwann cells towards replicative senescence. Remarkably, blocking this mechanism allows unrestricted proliferation, inducing malignant transformation of neurofibromas. Interestingly, our data suggest that in injured nerves, Schwann cells epigenetically activate the same locus to switch off proliferation and enter the senescence programme. Indeed, when this pathway is genetically blocked, Schwann cells fail to drop out of the cell cycle and continue to proliferate. We postulate that the Ink4a/Arf-locus is expressed as part of a physiological response that prevents uncontrolled proliferation of the de-differentiated Schwann cell generated during nerve regeneration, a response that is also activated to avoid overproliferation after tumorigenic stimuli in the peripheral nervous system.

JMJD3 as an epigenetic regulator in development and disease

“…JMJD3 can also direct MSCs to differentiate preferentially into one lineage over another lineage. Specifically, depletion of Jmjd3 leads to a decrease in osteogenic differentiation, while increasing adipogenic differentiation (Gomez-Sanchez et al, 2013). Studies implicating the involvement of microRNAs in MSC differentiation (Bengestrate et al, 2011; Inose et al, 2009; Li et al, 2008; Yang et al, 2011) has led to the discovery that the specific microRNA, MIR146A , interacts with the 3′ UTR of JMJD3 , inhibiting its function and decreasing osteogenesis (Huszar and Payne, 2014).…”

“…Tumorigenic stimuli or injury can lead to uncontrolled proliferation of Schwann cells, generating neurofibromas and schwannomas. Activation of JMJD3 leads to the removal of H3K27 marks from the Ink4a/Arf -locus and switches Schwann cells from a proliferative state to a senescent state to prevent overproliferation after nerve injury and during regeneration (Gomez-Sanchez et al, 2013). In this setting, JMJD3 plays a beneficial role in limiting tissue transformation and progression a pathological disease state.…”

“…Schwann cells myelinate axons in the peripheral nervous system and play a role in inherited demyelinating diseases. These cells are crucial for repair of the spinal cord and peripheral nerves, and JMJD3 limits Schwann cell overproliferation after nerve injury and during regeneration, thus protecting against neurofibroma (Gomez-Sanchez et al, 2013). Not only can JMJD3 affect the peripheral nervous system, it can also affect the central nervous system.…”

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity

“…To prevent SC overproliferation that could lead to tumor formation, the Arf/Ink4 locus is de-repressed by the HDM JMJD3 that demethylates H3K27 at the promoter of p19Arf and p16Ink4a and potentially also at the p15Ink4b promoter. These tumor-supressor proteins then inactivate SC proliferation [55].…”

“…To prevent SC overproliferation that could lead to tumor formation, the Arf/Ink4 locus is de-repressed by the HDM JMJD3 that demethylates H3K27 at the promoter of p19Arf and p16Ink4a and potentially also at the p15Ink4b promoter. These tumor-supressor proteins then inactivate SC proliferation [55].Even though the conversion of SCs into repair cells after lesion is efficient, it is interesting to point out that this process is not optimal and can be improved. Indeed, shortly after injury, HDAC2 is upregulated in SCs and mediates the assembly of a protein complex with the two H3K9 HDMs KDM3A and JMJD2C and the transcription factor Sox10, which is recruited to the Oct6 SCE to demethylate H3K9 and induce Oct6 transcription.…”