Regulation of Peripheral Myelination through Transcriptional Buffering of Egr2 by an Antisense Long Non-coding RNA

• Main Authors: Martinez-Moreno, Margot (Author), Zepecki, John P. (Author), Olaru, Alexander (Author), Ness, Jennifer K. (Author), Tapinos, Nikos (Author), O'Shea, Timothy Mark (Contributor), Langer, Robert S (Contributor)
• Other Authors: Massachusetts Institute of Technology. Institute for Medical Engineering & Science (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2018-04-24T17:20:56Z.
• Subjects: Article
• Online Access: Get fulltext

 Precise regulation of Egr2 transcription is fundamentally important to the control of peripheral myelination. Here, we describe a long non-coding RNA antisense to the promoter of Egr2 (Egr2-AS-RNA). During peripheral nerve injury, the expression of Egr2-AS-RNA is increased and correlates with decreased Egr2 transcript and protein levels. Ectopic expression of Egr2-AS-RNA in dorsal root ganglion (DRG) cultures inhibits the expression of Egr2 mRNA and induces demyelination. In vivo inhibition of Egr2-AS-RNA using oligonucleotide GapMers released from a biodegradable hydrogel following sciatic nerve injury reverts the EGR2-mediated gene expression profile and significantly delays demyelination. Egr2-AS-RNA gradually recruits H3K27ME3, AGO1, AGO2, and EZH2 on the Egr2 promoter following sciatic nerve injury. Furthermore, expression of Egr2-AS-RNA is regulated through ERK1/2 signaling to YY1, while loss of Ser184 of YY1 regulates binding to Egr2-AS-RNA. In conclusion, we describe functional exploration of an antisense long non-coding RNA in peripheral nervous system (PNS) biology. Keywords: nerve injury response; transcription; RNA epigenetics; antisense RNA; Egr2; myelination; YY1; neuregulin