Modification of internal adenosines in messenger RNA (mRNA) by methylation of the N6 position
(m6A) was first observed almost four decades
ago. Early work demonstrated that the m6A
modification was quite common, occurring at
an estimated frequency of three to five residues per mRNA. Nevertheless, the function,
if any, of this modification remained enigmatic. The cloning in 1997 of a subunit of the
RNA methylase complex (1) was followed
by a period of fitful inactivity before the field
reawakened in 2011 with the discovery of an
enzyme, FTO (fat mass and obesity-associ-ated protein), that was shown to catalyze the
demethylation of internal m6A residues (2).
The existence of a demethylase and the dem-
onstration that m6A levels were raised when
the enzyme was knocked down strongly
suggested that at least some m6A modifica-
tions were reversible and might be subject
to dynamic regulation. Since then, a series
of papers have appeared in rapid succession,
together providing a wealth of unequivocal
evidence for m6A function. But these findings
still have not led to a coherent picture of the
number and variety of functions of the m6A
Two recent RNA “methylome” studies
(3, 4) provide a transcriptome-wide map of
m6A-modified mRNAs. Both report the presence of m6A in about 7000 mRNAs, indicating that the modification is fairly promiscuous with regard to mRNA targets. However,
methylation is highly selective when considering which specific sites are modified.
Although both studies showed that methylation sites are largely confined to the consensus sequence Pu[G>A]m6AC[A/C/U], only
about 10% of sites conforming to this consensus are actually modified. Neither study
was able to determine the stoichiometry of
any specific modified site, nor could clusters
of modified sites be identified. Both studies
showed enrichment of modification sites near
stop codons; however, one study saw enrichment in long internal exons while the other
saw enrichment in 3′ untranslated regions.
Additionally, one study found elevated levels of m6A in the brain and
the other study did not. The reasons for these discrepancies are not
obvious. Nevertheless, both studies
found that modification sites were
well conserved between human
and mouse transcriptomes—a finding strongly suggestive of biological function. Indeed, knockdown of
the m6A methylase (3) resulted in
large-scale alterations in splicing
patterns, consistent with a striking
enrichment of m6A modifications
within alternatively spliced exons
(see the figure), with constitutive
Internal mRNA Methylation
Finally Finds Functions
Timothy W. Nilsen
Methylation of internal adenosine residues
in messenger RNA (mRNA) modulates mRNA
metabolism in both the nucleus and cytoplasm.
Center for RNA Molecular Biology, Case Western Reserve
University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA. E-mail: firstname.lastname@example.org
effect of the Antarctic ozone hole on the surface westerlies in the Southern Hemisphere.
Observational studies showed that the westerlies shifted poleward by several degrees of
latitude in recent decades, mainly in the Austral summer, and made a plausible connection
to the development of the ozone hole (10).
Comprehensive models provided important confirmation that the ozone hole does
move the westerlies poleward (11). A variety
of more idealized models are being used to
explore the pathways through which changes
in the stratosphere modify the surface winds,
demonstrating that the poleward shift of the
westerlies due to cooling of the polar stratosphere can be isolated from other parts of the
climate problem and related to fundamental
theories of atmospheric dynamics (12).
Increasing CO2 concentrations also push
the mid-latitude surface westerlies poleward
in climate models, complicating both the
quantitative attribution of the observed shift
(11) and the predictions of how the wester-
lies will evolve in the future as the ozone hole
heals and greenhouse gases continue to accu-
mulate. However, both comprehensive and
idealized climate models indicate that the
effects on the westerlies of greenhouse gases
and the ozone hole are linearly additive to a
first approximation. An underlying simplic-
ity in the forced climate change emerges here
as well, making prediction plausible.
A creative tension between simulation and
understanding, between accepting complex-
ity and searching for simplicity, is present in
many challenging scientific problems. Cli-
mate science provides an excellent example
of this tension. The most advanced compre-
hensive climate models effectively represent
the current ability to simulate the climate sys-
tem, and it is natural and appropriate to take
the output of those models as the basis for pre-
dicting the future climate. However, it is the
understanding of these responses—an under-
standing that depends on the presence of an
emergent simplicity in the forced response—
which provides a level of confidence that jus-
tifies advising policy-makers and the public
to pay heed to these predictions.
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2. A. Clement, P. DiNezio, Science 343, 976 (2014).
3. S. Sherwood, Q. Fu, Science 343, 737 (2014).
4. D. Rosenfeld, S. Sherwood, R. Wood, L. Donner, Science
343, 379 (2014).
5. E. G. Nisbet, E. J. Dlugokencky, P. Bousquet, Science 343,
6. G. A. Vecchi, G. Villarini, Science 343, 618 (2014).
7. D. S. Abbott, E. Tziperman, J. Atmos. Sci. 66, 519 (2009).
8. S. C. Sherwood, S. Bony, J.-L. Dufresne, Nature 505, 37
9. I. M. Held, Bull. Am. Meteorol. Soc. 86, 1609 (2005).
10. D. W. J. Thompson, S. Solomon, Science 296, 895
11. S.-W. Son et al., J. Geophys. Res. 115, D00M07 (2010).
12. C. I. Garfinkel, D.-Y. Waugh, E. P. Gerber, J. Clim. 26,
Methylating RNA regulates its function. A schematic diagram of
the RNA m6A methylation cycle. METTL3, methyltransferase-like 3.