mRNA Cap methylation in pluripotency and differentiation

Laura Grasso, Olga Suska, Lindsay Davidson, Thomas Gonatopoulos-Pournatzis, Ritchie Williamson, Lize Wasmus, Simone Wiedlich, Mark Peggie, Marios P. Stavridis, Victoria H. Cowling (Lead / Corresponding author)

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1352-1365
Number of pages14
JournalCell Reports
Volume16
Issue number5
Early online date21 Jul 2016
DOIs
Publication statusPublished - 2 Aug 2016

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Methylation
Random access storage
Messenger RNA
Genes
Gene expression
Ubiquitination
Methyltransferases
Fibroblasts
Embryonic Stem Cells
Stem cells
Transcriptome
Serine
Cell Differentiation
Gene Expression
Degradation
Processing

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Grasso, L., Suska, O., Davidson, L., Gonatopoulos-Pournatzis, T., Williamson, R., Wasmus, L., ... Cowling, V. H. (2016). mRNA Cap methylation in pluripotency and differentiation. Cell Reports, 16(5), 1352-1365. https://doi.org/10.1016/j.celrep.2016.06.089
Grasso, Laura ; Suska, Olga ; Davidson, Lindsay ; Gonatopoulos-Pournatzis, Thomas ; Williamson, Ritchie ; Wasmus, Lize ; Wiedlich, Simone ; Peggie, Mark ; Stavridis, Marios P. ; Cowling, Victoria H. / mRNA Cap methylation in pluripotency and differentiation. In: Cell Reports. 2016 ; Vol. 16, No. 5. pp. 1352-1365.
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Grasso, L, Suska, O, Davidson, L, Gonatopoulos-Pournatzis, T, Williamson, R, Wasmus, L, Wiedlich, S, Peggie, M, Stavridis, MP & Cowling, VH 2016, 'mRNA Cap methylation in pluripotency and differentiation', Cell Reports, vol. 16, no. 5, pp. 1352-1365. https://doi.org/10.1016/j.celrep.2016.06.089

mRNA Cap methylation in pluripotency and differentiation. / Grasso, Laura; Suska, Olga; Davidson, Lindsay; Gonatopoulos-Pournatzis, Thomas; Williamson, Ritchie; Wasmus, Lize; Wiedlich, Simone; Peggie, Mark; Stavridis, Marios P.; Cowling, Victoria H. (Lead / Corresponding author).

In: Cell Reports, Vol. 16, No. 5, 02.08.2016, p. 1352-1365.

Research output: Contribution to journalArticle

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AU - Grasso, Laura

AU - Suska, Olga

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AU - Wasmus, Lize

AU - Wiedlich, Simone

AU - Peggie, Mark

AU - Stavridis, Marios P.

AU - Cowling, Victoria H.

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N2 - 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.

AB - 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.

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VL - 16

SP - 1352

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JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

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Grasso L, Suska O, Davidson L, Gonatopoulos-Pournatzis T, Williamson R, Wasmus L et al. mRNA Cap methylation in pluripotency and differentiation. Cell Reports. 2016 Aug 2;16(5):1352-1365. https://doi.org/10.1016/j.celrep.2016.06.089