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RNA Modifications Modulate Gene Expression During Development


RNA Modifications Modulate Gene Expression During Development

Michaela Frye et al. Science.


RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programs. They affect diverse eukaryotic biological processes, and the correct deposition of many of these modifications is required for normal development. Messenger RNA (mRNA) modifications regulate various aspects of mRNA metabolism. For example, N 6-methyladenosine (m6A) affects the translation and stability of the modified transcripts, thus providing a mechanism to coordinate the regulation of groups of transcripts during cell state maintenance and transition. Similarly, some modifications in transfer RNAs are essential for RNA structure and function. Others are deposited in response to external cues and adapt global protein synthesis and gene-specific translational accordingly and thereby facilitate proper development.

Conflict of interest statement

Competing interests: C.H. is a scientific founder of Accent Therapeutics and a member of its scientific advisory board. M.F. consults for Storm Therapeutics. All other authors declare no competing financial interests.


Fig. 1.
Fig. 1.. Regulation of gene expression by RNA modifications.
(A) m6A is installed by a multicomponent writer complex with the catalytic subunit METTL3 and removed by the demethylase enzymes FTO and ALKBH5. m6A reader proteins can specifically bind m6A transcripts and effect different outcomes for methylated mRNAs. (B) RNA modifications in human eukaryotic tRNAs according to Modomics ( xU, other modified uracil (U); N, unknown modified. How often a base is modified is shown by the grayscale. Only examples of writers (TRMT6/61, DNMT2, NSUN2, NSUN3, PUS7, and Elongator) and erasers (ALKBH1) are shown and how they affect translation. Modifications at the wobble base are most diverse.
Fig. 2.
Fig. 2.. RNA modifications regulate cell differentiation and development.
(A) Model for the roles of m6A in cell differentiation. In the naïve, undifferentiated state, cell state–specific master transcription factors recruit the METTL3 complex to methylate transcripts that encode cell fate factors. Translation of these methylated factors may aid in the maintenance of cell state and prevent differentiation. When cells initiate differentiation and switch their transcriptional program, reader proteins mediate the turnover of the methylated transcripts to facilitate transcriptome switching. (B) Modification by NSUN2, DNMT2, and PUS7 protects tRNAs from cleavage and production of tRFs, which enables high global translation. In a different cell state, tRFs can affect global and gene-specific protein translation by displacing distinct RBPs and are therefore important players in stem cell differentiation. Wobble tRNA modifications—for example, by NSUN3 and Elongator—enhance the versatility of tRNA anticodon to recognize mRNA to optimize codon usage and translation of cytoplasmic and mitochondrial mRNAs during differentiation.
Fig. 3.
Fig. 3.. Future directions for research into gene regulation by RNA modifications.
There are several unresolved questions in the field: Mechanistically, how do external stimuli regulate RNA modification to affect protein translation rates and transcription? How do RNA modifying enzymes act as metabolic sensors? How do RNA modifications directly or indirectly regulate chromatin regulatory complexes to affect chromatin state or transcription? What factors—such as transcription factors, chromatin, RNA, RBPs, or components of the RNA polymerase II complex— recruit m6A writer and eraser enzymes to their targets? What factors regulate and determine the target specificity of readers? How are the protein synthesis and transcription machineries coordinated by RNA modifications?

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