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

Cell Rep. 2017 Aug 22;20(8):1950-1963. doi: 10.1016/j.celrep.2017.07.068.

Abstract

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: Egr2; RNA epigenetics; YY1; antisense RNA; myelination; nerve injury response; neuregulin; transcription.

MeSH terms

  • Animals
  • Early Growth Response Protein 2 / genetics*
  • Early Growth Response Protein 2 / metabolism
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myelin Sheath / metabolism*
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Transcription Factors
  • Transfection

Substances

  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • RNA, Long Noncoding
  • Transcription Factors