title: mRNA Cap Methylation in Pluripotency and Differentiation.
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.
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Grasso
authors.affiliation: Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Olga
authors.initials: O
authors.lastname: Suska
authors.affiliation: Human Pluripotent Stem Cell Facility, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Davidson
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gonatopoulos-Pournatzis
authors.affiliation: School of Pharmacy, Faculty of Life Sciences, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK.
authors.forename: Ritchie
authors.initials: R
authors.lastname: Williamson
authors.affiliation: MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Lize
authors.initials: L
authors.lastname: Wasmus
authors.affiliation: Department of Signal Transduction Therapies, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Simone
authors.initials: S
authors.lastname: Wiedlich
authors.affiliation: Department of Signal Transduction Therapies, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Peggie
authors.affiliation: Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Marios P
authors.initials: MP
authors.lastname: Stavridis
authors.affiliation: 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.
authors.forename: Victoria H
authors.initials: VH
authors.lastname: Cowling
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D020935:MAP Kinase Signaling System / Q000235:genetics; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D054875:Ubiquitination / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D046988:Proteasome Endopeptidase Complex