Epigenetic and Transcriptional Regulation of Axon Regeneration
We are studying the mechanisms by which a pro-regenerative state is reprogrammed following axon injury in sensory neurons. We discovered that increased histone acetylation following the nuclear export of HDAC5 is required for axon regeneration in sensory neurons. This study represents a pioneering discovery in the field of axon regeneration, which identified a global epigenetic mechanism by which injured neurons transition to a pro-regenerative state. Because epigenetic modifications affect globally, yet specifically a combination of multiple genes, they represent ideal strategies to promote neural repair.
We also discovered a critical role for the transcription factor HIF-1α in axon regeneration. We found that HIF-1α co-coordinates the expression of multiple pro-regenerative genes. Because low oxygen levels (hypoxia) can increase HIF-1α levels, we found that hypoxia accelerates axon regeneration. This study brings a novel and important contribution to the field of axon regeneration.
We continue to employ a combination of approaches, including phenotypic genetic and drug screens combined with RNAseq and ATACseq studies in defined neuronal populations to understand how a pro-regenerative state can be activated after axon injury. We hope to reveal strategies to initiate the pro-regenerative program and stimulate robust and meaningful long-distance axon regeneration in the injured nervous system.
Although expression of regeneration-associated genes is essential to activate the axon regeneration program, much less is known about the contribution of gene inactivation. We recently demonstrated that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. 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. Mechanistically, we showed that the epigenetic regulator ubiquitin like containing PHD ring finger 1 (UHRF1) interacts with DNA methyltransferases (DNMTs) to repress the expression of the tumor suppressor genes 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. This study also provides a better understanding of the transient gene regulatory networks employed by peripheral neurons to promote axon regeneration. We are pursuing our studies on the role of DNA methylation in neuronal injury responses.