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m 6 A enhances the phase separation potential of mRNA.
- Source :
-
Nature [Nature] 2019 Jul; Vol. 571 (7765), pp. 424-428. Date of Electronic Publication: 2019 Jul 10. - Publication Year :
- 2019
-
Abstract
- N <superscript>6</superscript> -methyladenosine (m <superscript>6</superscript> A) is the most prevalent modified nucleotide in mRNA <superscript>1,2</superscript> , with around 25% of mRNAs containing at least one m <superscript>6</superscript> A. Methylation of mRNA to form m <superscript>6</superscript> A is required for diverse cellular and physiological processes <superscript>3</superscript> . Although the presence of m <superscript>6</superscript> A in an mRNA can affect its fate in different ways, it is unclear how m <superscript>6</superscript> A directs this process and why the effects of m <superscript>6</superscript> A can vary in different cellular contexts. Here we show that the cytosolic m <superscript>6</superscript> A-binding proteins-YTHDF1, YTHDF2 and YTHDF3-undergo liquid-liquid phase separation in vitro and in cells. This phase separation is markedly enhanced by mRNAs that contain multiple, but not single, m <superscript>6</superscript> A residues. Polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their low-complexity domains and thereby leading to phase separation. The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated compartments, such as P-bodies, stress granules or neuronal RNA granules. m <superscript>6</superscript> A-mRNA is subject to compartment-specific regulation, including a reduction in the stability and translation of mRNA. These studies reveal that the number and distribution of m <superscript>6</superscript> A sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome, and suggest that the cellular properties of m <superscript>6</superscript> A-modified mRNAs are governed by liquid-liquid phase separation principles.
- Subjects :
- Adenosine metabolism
Animals
Biological Transport
Cell Line
Cytoplasmic Granules chemistry
Cytoplasmic Granules metabolism
Humans
Methylation
Methyltransferases deficiency
Mice
Phase Transition
RNA, Messenger analysis
RNA-Binding Proteins chemistry
RNA-Binding Proteins metabolism
Stress, Physiological
Adenosine analogs & derivatives
Cell Compartmentation
RNA, Messenger chemistry
RNA, Messenger metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 571
- Issue :
- 7765
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 31292544
- Full Text :
- https://doi.org/10.1038/s41586-019-1374-1