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Cell Rep. 2016 Aug 2;16(5):1352-1365. doi: 10.1016/j.celrep.2016.06.089. Epub 2016 Jul 21.

mRNA Cap Methylation in Pluripotency and Differentiation.

Author information

1
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
2
Human Pluripotent Stem Cell Facility, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
3
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
4
School of Pharmacy, Faculty of Life Sciences, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK.
5
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
6
Department of Signal Transduction Therapies, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
7
Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
8
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK. Electronic address: v.h.cowling@dundee.ac.uk.

Abstract

The mRNA cap recruits factors essential for transcript processing and translation initiation. We report that regulated mRNA cap methylation is a feature of embryonic stem cell (ESC) differentiation. Expression of the mRNA cap methyltransferase activating subunit RAM is elevated in ESCs, resulting in high levels of mRNA cap methylation and expression of a cohort of pluripotency-associated genes. During neural differentiation, RAM is suppressed, resulting in repression of pluripotency-associated factors and expression of a cohort of neural-associated genes. An established requirement of differentiation is increased ERK1/2 activity, which suppresses pluripotency-associated genes. During differentiation, ERK1/2 phosphorylates RAM serine-36, targeting it for ubiquitination and proteasomal degradation, ultimately resulting in changes in gene expression associated with loss of pluripotency. Elevated RAM expression also increases the efficiency of fibroblast reprogramming. Thus, the mRNA cap emerges as a dynamic mark that instructs change in gene expression profiles during differentiation and reprogramming.

PMID:
27452456
PMCID:
PMC4977272
DOI:
10.1016/j.celrep.2016.06.089
[Indexed for MEDLINE]
Free PMC Article

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