Regulation of Gene Expression by N6-methyladenosine in Cancer

doi:10.1016/j.tcb.2019.02.008

Trends in Cell Biology

Volume 29, Issue 6, June 2019, Pages 487-499

https://doi.org/10.1016/j.tcb.2019.02.008 Get rights and content

Highlights

m⁶A is the most abundant mRNA modification and it regulates many aspects of RNA metabolism, including RNA splicing, export, translation, and decay.
Numerous recent studies indicate an important role for m⁶A in regulating gene expression in multiple physiologic processes, such as stress responses, stem cell differentiation, gametogenesis, and T cell homeostasis.
Aberrant m⁶A mRNA methylation, through the altered expression of m⁶A writer, eraser, or reader proteins, has also been associated with several cancers.
m⁶A has been reported to affect gene expression in cancer cells through many different pathways. In some studies, increased m⁶A methylation appears to contribute to cancer cell tumorigenicity by enhancing translation of oncogenes or degrading tumor suppressor genes. Other studies observe that m⁶A helps inhibit the expression of oncogenes, suggesting tumor suppressing roles for m⁶A methylation.

As the most abundant mRNA modification in eukaryotic cells, N⁶-methyladenosine (m⁶A) has recently emerged as an important regulator of gene expression. m⁶A modification can be deposited by m⁶A methyltransferases, removed by m⁶A demethylases, and recognized by different reader proteins. Numerous lines of evidence have shown that m⁶A methylation plays critical roles regulating gene expression in development and disease. In this review, we summarize the molecular and cellular function of m⁶A and highlight some key results which demonstrate the role of m⁶A in various cancers. Finally, we discuss future directions for research into m⁶A and its effects in cancer and the potential for targeting RNA modification in cancer treatment.

Section snippets

N⁶-Methyladenosine (m⁶A) in Messenger RNA

In the central dogma of molecular biology, genetic information is stored in DNA, transcribed into RNA, and then expressed through the function of protein. Parallel to the known roles of DNA and protein modifications in gene regulation, recent work has illuminated the regulation of RNA metabolism through processes such as RNA modification and editing as important post-transcriptional regulatory mechanisms [1]. Among hundreds of known RNA modifications, m⁶A is the most prevalent internal

Molecular Functions of m⁶A in Post-transcriptional Gene Regulation

m⁶A has been shown to affect almost every stage of mRNA processing, including splicing, export, translation, and decay. Mechanistically, different sets of m⁶A-specific reader proteins recognize m⁶A methylated transcripts to effect these changes in mRNA metabolism (Figure 1).

Multiple Physiologic Functions of m⁶A

Given the dynamic reversibility of m⁶A methylation and its many roles in post-transcriptional regulation, it has been reported to play an important role in numerous physiological processes.

Varying Roles of m⁶A in Cancer

Consistent with the important role of m⁶A mRNA modification in regulating gene expression in various biological processes, aberrant m⁶A modification is associated with a variety of human cancers. However, knowledge of the mechanistic link between m⁶A and human carcinogenesis is limited. While investigations addressing this issue are still at an early stage, efforts are underway to explore the biological impacts of m⁶A modifications in cancer. In particular, both elevated and decreased levels of

Concluding Remarks

RNA modification is a new layer of post-transcriptional gene regulation that is important in various aspects of biology, including cancer. In many cases, the roles of m⁶A in regulating gene expression in cancer mirror the physiological roles of m⁶A in development and normal tissue homeostasis. A variety of studies have identified essential roles for m⁶A methylation in regulating cell differentiation, for example, mediating transcriptome turnover during critical cell fate transitions in the

Outstanding Questions

Different studies find differing effects of m⁶A methylation on tumor progression. Some studies suggest it promotes cancer, while others suggest a tumor suppressing role for m⁶A methylation. What mechanisms govern the different effects of m⁶A in different cancer types and subtypes?

In cancers affected by aberrant m⁶A methylation, what are the key transcripts whose altered expression mediates the effects of altered m⁶A methylation on carcinogenesis and tumor progression? What regulators determine

Acknowledgements

B.T.H is supported by National Cancer Institute fellowship F32 CA221007. C.H is supported by the National Institutes of Health (HG008935 and GM071440). C.H. is an investigator of the Howard Hughes Medical Institute.

Disclaimer Statement

C.H. is a scientific founder and a scientific advisory board member of Accent Therapeutics, Inc.

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The importance of N6-methyladenine (m6A) in mRNA metabolism, physiology, pathology and other life processes is well recognized. However, the exact role of m6A regulators in primary Sjögren's syndrome (PSS) remains unclear. In this study, we used bioinformatics and machine learning random forest approach to screen eight key m6A regulators from the Gene Expression Omnibus GSE7451, GSE40611 and GSE84844 datasets. An accurate nomogram model for predicting PSS risk was established based on these regulators. And using consensus clustering, patients diagnosed with PSS were classified into two different m6A patterns. We found that patients in group B had higher m6A scores compared to those in group A: furthermore, both groups were closely related to immunity and possibly to other diseases. These results emphasise the important role of m6A regulators in the pathogenesis of PSS. Our study of m6A patterns may inform future immunotherapy strategies for PSS.
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⁴: These authors contributed equally to this work.

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Trends in Cell Biology

ReviewRegulation of Gene Expression by N6-methyladenosine in Cancer

Highlights

Section snippets

N6-Methyladenosine (m6A) in Messenger RNA

Molecular Functions of m6A in Post-transcriptional Gene Regulation

Multiple Physiologic Functions of m6A

Varying Roles of m6A in Cancer

Concluding Remarks

Outstanding Questions

Acknowledgements

Disclaimer Statement

Cell

Mol. Cell

Cell

Cell

Cell Rep.

Mol. Cell

Cell

Cell

Cell

Cell

Mol. Cell

Cell Stem Cell

Cell Stem Cell

Cancer Cell

J. Biol. Chem.

Cell Rep.

Cancer Lett.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Mol. Cell

Cell Rep.

Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells

Proc. Natl. Acad. Sci. U. S. A.

Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs

EMBO Rep.

The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention

Cell

PCIF1 catalyzes m6Am mRNA methylation to regulate gene expression

bioRxiv

Identification of the m6Am methyltransferase PCIF1 reveals the location and functions of m6Am in the transcriptome

bioRxiv

Cap-specific, terminal N6-methylation by a mammalian m6Am methyltransferase

Cell Res.

Cap-specific terminal N6-methylation of RNA by an RNA polymerase II–associated methyltransferase

Science

N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO

Nat. Chem. Biol.

N6-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions

Nature

The methylation state of poly A-containing messenger RNA from cultured hamster cells

Nucleic Acids Res.

Modified nucleosides and bizarre 5′-termini in mouse myeloma mRNA

Nature

Grand challenge commentary: RNA epigenetics?

Nat. Chem. Biol.

Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq

Nature

Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism

Cell Res.

RNA modifications modulate gene expression during development

Science

Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase

Cell Res.

m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation

Science

m(6)A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover

Genes Dev.

FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis

Cell Res.

N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3′-end processing

Nucleic Acids Res.

N6-methyladenosine marks primary microRNAs for processing

Nature

YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs

eLife

The m6A-methylase complex recruits TREX and regulates mRNA export

Sci. Rep.

YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA

Review
Regulation of Gene Expression by N⁶-methyladenosine in Cancer

N⁶-Methyladenosine (m⁶A) in Messenger RNA

Molecular Functions of m⁶A in Post-transcriptional Gene Regulation

Multiple Physiologic Functions of m⁶A

Varying Roles of m⁶A in Cancer

Human METTL16 is a N⁶-methyladenosine (m⁶A) methyltransferase that targets pre-mRNAs and various non-coding RNAs

The U6 snRNA m⁶A methyltransferase METTL16 regulates SAM synthetase intron retention

PCIF1 catalyzes m⁶Am mRNA methylation to regulate gene expression

Identification of the m⁶Am methyltransferase PCIF1 reveals the location and functions of m⁶Am in the transcriptome

Cap-specific, terminal N⁶-methylation by a mammalian m⁶Am methyltransferase

Cap-specific terminal N⁶-methylation of RNA by an RNA polymerase II–associated methyltransferase

N⁶-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO

N⁶-methyladenosine-dependent RNA structural switches regulate RNA–protein interactions

Topology of the human and mouse m⁶A RNA methylomes revealed by m⁶A-seq

Dynamic transcriptomic m⁶A decoration: writers, erasers, readers and functions in RNA metabolism

Mammalian WTAP is a regulatory subunit of the RNA N⁶-methyladenosine methyltransferase

m⁶A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation

FTO-dependent demethylation of N⁶-methyladenosine regulates mRNA splicing and is required for adipogenesis

N⁶-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3′-end processing

N⁶-methyladenosine marks primary microRNAs for processing

YTHDC1 mediates nuclear export of N⁶-methyladenosine methylated mRNAs

The m⁶A-methylase complex recruits TREX and regulates mRNA export

YTHDF3 facilitates translation and decay of N⁶-methyladenosine-modified RNA

Cytoplasmic m⁶A reader YTHDF3 promotes mRNA translation

Dynamic m⁶A mRNA methylation directs translational control of heat shock response

m⁶A facilitates eIF4F-independent mRNA translation

N⁶-methyladenosine guides mRNA alternative translation during integrated stress response