In:
Pain, Ovid Technologies (Wolters Kluwer Health), Vol. 162, No. 7 ( 2021-07), p. 1960-1976
Abstract:
The methyltransferase-like 3 ( Mettl3 ) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m 6 A) modification, which plays an important role in gene post-transcription modulation. Although RNA m 6 A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m 6 A level and m 6 A writer Mettl3 in the spinal cord. Mimicking this decease by knocking down or conditionally deleting spinal Mettl3 elevated the levels of m 6 A in ten-eleven translocation methylcytosine dioxygenases 1 ( Tet1 ) mRNA and TET1 protein in the spinal cord, leading to production of pain hypersensitivity. By contrast, overexpressing Mettl3 reversed a loss of m 6 A in Tet1 mRNA and blocked the CFA-induced increase of TET1 in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m 6 A reader, stabilized upregulation of spinal TET1 because of the reduction of Tet1 mRNA decay by the binding to m 6 A in Tet1 mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.
Type of Medium:
Online Resource
ISSN:
0304-3959
,
1872-6623
DOI:
10.1097/j.pain.0000000000002218
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2021
detail.hit.zdb_id:
1494115-6
