Melatonin restores the pluripotency of long-term-cultured embryonic stem cells through melatonin receptor-dependent m6A RNA regulation
- 1 September 2020
- journal article
- research article
- Published by Wiley in Journal of Pineal Research
- Vol. 69 (2), e12669
- https://doi.org/10.1111/jpi.12669
Abstract
N6-methyladenosine (m6A) methylation is the most common and abundant modification on mammalian messenger RNA (mRNA) and regulates the pluripotency of embryonic stem cells (ESCs). Research has shown that melatonin plays a fundamental role in DNA and histone modifications. However, the effect of melatonin on RNA modification is unknown. Here, for the first time, we investigated the effect of melatonin on m6A modifications in long-term-cultured ESCs. Pluripotency studies indicated that 10 mu mol/L melatonin sufficiently maintained ESCs with stemness features over 45 passages (more than 90 days). Notably, treatment of ESCs with melatonin led to a significant decrease in the nuclear presence of m6A methyltransferase complex and decreased global m6A modification. Depletion of melatonin receptor 1 (MT1) by CRISPR/Cas9 significantly reduced the effects of melatonin on ESC pluripotency and m6A modification. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) revealed that melatonin promotes stabilization of core pluripotency factors, such as Nanog, Sox2, Klf4, and c-Myc, by preventing m6A-dependent mRNA decay. Using cell signaling pathway profiling systems, melatonin was shown to regulate m6A modification predominantly through the MT1-JAK2/STAT3-Zfp217 signal axis. This study reveals a new dimension regarding melatonin regulation of gene expression at the RNA level.Keywords
This publication has 66 references indexed in Scilit:
- Zscan4 restores the developmental potency of embryonic stem cellsNature Communications, 2013
- On the free radical scavenging activities of melatonin's metabolites, AFMK and AMKJournal of Pineal Research, 2012
- Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop CodonsCell, 2012
- Topology of the human and mouse m6A RNA methylomes revealed by m6A-seqNature, 2012
- Association of telomere length with authentic pluripotency of ES/iPS cellsCell Research, 2011
- Zscan4 regulates telomere elongation and genomic stability in ES cellsNature, 2010
- A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cellsNature, 2009
- Linking DNA methylation and histone modification: patterns and paradigmsNature Reviews Genetics, 2009
- Epigenetic regulation: a new research area for melatonin?Journal of Pineal Research, 2007
- MelatoninThe FEBS Journal, 2006