dynamic rna modifications in disease

Dynamic RNA modifications in diseaseArne Klungland1,2 and John Arne Dahl1,3

Available online at www.sciencedirect.com

ScienceDirect

While the presence of 6-methyladenosine (m6A) modifications

in mRNA was noted several decades ago, the first enzyme

reversing this modification was identified very recently. Today

we know of two methyltransferases introducing m6A in

mRNA — METTL3 and METTL14 — and two demethylases

that remove it have been identified — FTO (ALKBH9) and

ALKBH5. The conserved role of m6A seems to relate to

meiosis, and mice lacking ALKBH5 are infertile. While loss-of-

function mutation in FTO causes a recessive lethal syndrome,

sequence variants in introns of the FTO gene are associated

with obesity and type 2 diabetes.

Addresses1 Clinic for Diagnostics and Intervention and Institute of Medical

Microbiology, Oslo University Hospital, Rikshospitalet, Sognsvannsveien

20, 0027 Oslo, Norway2 Institute of Basic Medical Sciences, University of Oslo, 0315 Oslo,

Norway

Corresponding author: Klungland, Arne ([email protected])3Current address: Ludwig Institute for Cancer Research, La Jolla, CA

92093, USA.

Current Opinion in Genetics & Development 2014, 26:47–52

This review comes from a themed issue on Molecular and genetic

bases of disease

Edited by Cynthia T McMurray and Jan Vijg

http://dx.doi.org/10.1016/j.gde.2014.05.006

0959-437X # 2014 Published by Elsevier Ltd. All right reserved.

IntroductionA broad repertoire of modifications is known to underlie

the adaptable coding and structural function of proteins,

DNA and various RNA species. Methylations of mam-

malian DNA and histone residues are known to impact

regulation of transcription and the discoveries of

demethylases that remove methylation in DNA and

histones provide a basis for the understanding of dynamic

regulation of mammalian gene expression. The discovery

of these demethylases has led to significant progress in

the understanding of methyl marks in gene regulation and

the role of dynamic regulation in numerous diseases [1–6]. In mRNA, the m6A modification is particularly inter-

esting since it is the most abundant internal modification

and each mRNA contains on average from three to five

m6A modifications [7]. In prokaryotes, the m6A base

modification in DNA is a well-known epigenetic mark

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that influences many cellular processes [8], while m6A

seems to be absent from mammalian DNA. Early reports

indicate that the m6A modification in mRNA is installed

by a single methyltransferase complex with METTL3

(MT-A70) as the critical S-adenosyl-L-methionine

(SAM)-binding component [9–11]. The sequence speci-

ficity of this methyltransferase is not absolute, however,

m6A is only found on the degenerate consensus sequence

RR-m6A-CH (R = purine, H = C, A or U), yet, only a

fraction of consensus sequences is methylated [12,13].

Recently, two laboratories used a novel antibody-based

approach for methylated RNA immunoprecipitation com-

bined with massively parallel sequencing [14��,15��].These comprehensive analyses of mRNA methylation

revealed a distinct pattern of the m6A topology.

While 5-methylcytosine (5mC), and products thereof,

represent the key base modifications in DNA; cellular

RNAs, such as mRNA, tRNA, rRNA, and snRNA, have

long been known to contain more than 100 structurally

different base modifications [16]. Indeed, ALKBH8 was

previously shown to be required for the biogenesis of

multiple tRNA wobble uridine modifications [17–20].

The exact function of many of these RNA modifications

remains elusive, yet some are directly linked with human

diseases [21–23]; reviewed in [24]. It has been speculated

that some RNA modifications could be dynamic and have

regulatory roles analogous to modifications of proteins and

DNA [25]. Recently the m6A modification in mRNA was

given increased attention after it was demonstrated to be

a dynamic mark. This modification also exists in other

RNA species like tRNA [26] and rRNA [27].

Studies in model organisms, as well as in humans, points

toward important roles of m6A in cellular homeostasis.

Additionally, inactivation of enzymes required for

m6A demethylation cause obvious pathologies in mice

and men. In this short review, we will describe novel

findings on the dynamics of m6A and its role in disease

(Figure 1).

Topology of 6-methyladenosine (m6A) in mRNAAlthough the abundance of m6A in mRNA has been

known for a long time, a method for globally identifying

the m6A sites was only established recently. In 2012, two

independent laboratories reported on the distribution of

m6A in mRNA [14��,15��]. Both these studies developed

an antibody-based method for enrichment of m6A sites

combined with high throughput sequencing. More than

7000 human genes were recognized as m6A containing,

and m6A sites are particularly enriched around stop

codons. Sites were also found at 30 UTRs and within


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48 Molecular and genetic bases of disease

Figure 1

N

N

NN

N

N

NN

HN

HN

RNA

RNA

RNA

RNA

O

OO

N N

NN

RNA

OH

RNA

OO

O

OO

OO

CHH

OH

OH

FTO loss-of-function in humans cause severe growthretardation and multiple malformations [55].

MUTANT AND POLYMORPHIC VARIANTS OF m6ADEMETHYLASES

MUTANT ORGANISMS FOR COMPONENTS OF THE m6A METHYLTRANSFERASE COMPLEX

CH3

NH2

CH2OH

m6Adenosine

hm6Adenosine

Adenosine

Hydroxylases(demethylases)

FTO andALKBH5

+O2,Fe(II)/α-KG

Methyltransferase complexMETTL3,METTL14,

WTAP, and more+

S-Adenosy-L-methionine

Formaldehyde

ALKBH5 inactivation in mice causes female and male infertility and increased amount of internal m6A modifications in mRNA [29].

Polymorphic variants in the human FTO gene and FTO overexpression in mice leads to obesity, [52-54, 57].

IME4 is required for sporulation in S. Cerevisiae and induction of sporulation leads to appearence of m6A in yeast mRNA [47].

IME4 is expressed in testes and ovaries of D. Melanogaster and is required for viability. Hypomorphic IME4 alleles reveal critical functions in oogenesis [49].

MTA is required for the developing embryo of Arabidopsis. MTA expression strongly correlates with dividing tissues, particularly in reproductive organs [48].

WTAP, a subunit of the mammalian methyltransferase complex, is required for differentiation of endoderm and mesoderm in the mosue embryo and WTAPmutant embryos dies at day 6.5 - 10.5 [50-51].

FTO inactivation in mice leads to growth retardation, infertility and protects from obesity [56].

Current Opinion in Genetics & Development

Methylation and demethylation of 6-methyladenosine (m6A) in mRNA. Methylation of internal adenosines in mRNA is most likely catalyzed by a single

methyltransferase complex of which METTL3 is the S-adenosyl-L-methionine (SAM)-binding component. FTO and ALKBH5 catalyze the oxidative

demethylation of m6A in mRNA with hydroxymethyladenosine (hm6A) as a predictable unstable intermediate. FTO and ALKBH5 are iron(II)/a-KG-

dependent dioxygenases, which use their iron(II) center and the a-KG cofactor to activate dioxygen. The unstable oxidized intermediate, hm6A, then

spontaneously releases formaldehyde, resulting in the removal of the methyl group from adenine. The phenotypes of mutant organisms lacking genes

required for m6A dynamics are specified.

long internal exons. Importantly, m6A sites were found to

be highly conserved between humans and mice. These

data strongly support a fundamental regulatory role of

m6A. More recently, a high-resolution map of m6A modi-

fications in meiotic yeast transcripts was obtained [28��].These results reveal a dynamically regulated mRNA

methylome in yeast meiosis, and this study is of particular

interest for mammalian studies where the enzymatic

reversion of m6A to adenosine (A) seems to be essential

for successful spermatogenesis and oogenesis [29��]. Cur-

rently, several protocols are being developed for the

identification of m6A in the transcriptome [30,31].


Writers and erasers of 6-methyladenosine(m6A) in mRNAThe m6A modification in mammalian mRNA is most

likely installed by a single methyltransferase complex

and METTL3 (MT-A70) was early identified as the

candidate S-adenosyl-L-methionine (SAM)-binding com-

ponent of this complex [9]. Recently, affinity purification

of tagged-METTL3 led to the identification of

METTL14, thus suggesting that the methyltransferase

complex contains two active methyltransferase subunits

[32��]. At the same time, two other publications described

the identification of the METTL14 methyltransferase by


Dynamic RNA modifications in disease Klungland and Dahl 49

sequence homology search [33��,34�]. The METTL3 and

METTL14 methyltransferases are not well character-

ized, though it seems that they have overlapping func-

tions and downregulation of METTL3 and METTL14 in

stem cells led to similar phenotypes. WTAP has been

identified as a third member of the methyltransferase

complex and is required for the localization of METTL3

and METTL14 to nuclear speckles and downregulation

of WTAP affects the cellular m6A level [32��,33��]. The

mammalian methyltransferase complex probably con-

tains numerous essential proteins yet to be identified.

In 2011, it was reported that the fat mass and obesity-

associated FTO protein catalyzes the removal of m6A

from RNA in vitro and in vivo [35��]. This was the first

example of reversible RNA methylation. The oxidation

of m6A by FTO has later been described in more detail.

FTO also generates the two additional intermediate

modifications, 6-hydroxymethyladenosine (hm6A) and

6-formyladenosine (f6A), and, importantly, both of these

products have been identified in vivo [36]. FTO is a

distantly related member of the mammalian AlkB family

and is also identified as ALKBH9. ALKBH5 was reported

as a second m6A demethylase and a lack of ALKBH5 in

mice lead to a remarkable upregulation of m6A in mRNA

in vivo [29��]. In contrast, the role of FTO in demethylat-

ing m6A in vivo has not been firmly established and FTO

has the ability to demethylate several modifications in

single-stranded DNA and RNA in vitro [37,38].

A few reports on the structure of m6A demethylases,

FTO and ALKBH5 have been published and they all

identify a loop that confers single-stranded RNA or DNA

selectivity [39�,40–42]. While the structure of FTO is in a

complex with the mononucleotide 3-methyltymine

(m3T) no structures have yet been obtained with

RNA-oligoes containing the relevant modified base.

Readers of 6-methyladenosine (m6A) in mRNA6-Methyladenosine appears to have biochemical proper-

ties similar to adenosine. Thus, it seems likely that the

role of m6A is executed through proteins and other RNAs

that bind at specific m6A sites. A breakthrough in this

direction was the discovery of the selective recognition of

m6A by the human YTH domain family 2 (YTHDF2)

protein [43��]. YTHDF2 regulates mRNA degradation

and has over 3000 cellular RNA targets, including

mRNAs and non-coding RNAs. The RNA-Binding

Protein DataBase (RBPDB) includes 422 human proteins

[44]. While some of these have sequence specificities

excluding them from being specific for m6A recognition,

others might well require m6A for selective binding [45].

Indeed, there is a good overlap between m6A peaks in the

untranslated 30 region of mRNAs and known regions for

RNA regulatory elements [15��]. Also, it might well be

that m6A affects the binding of miRNA [46].


Mutant organisms and diseaseEarly studies in yeast failed to identify m6A in mRNA.

However, the IME4 (Inducer of MEiosis 4) gene of

S. cerevisiae is very similar to the mammalian m6A methyl-

transferase subunit and the amount of IME4 mRNA is

greatly elevated during sporulation and in the stationary

phase [47]. With this information, an increased level of

m6A was detected in both vegetative and sporulating

yeast cells [47]. Mutations in the catalytic domain of

IME4 cause defective sporulation. Similarly, studies of

the METTL3 homolog in Arabidopsis and Drosophilamutants point toward a conserved role for m6A in game-

togenesis [48,49] Unlike yeast, the m6A methyltransfer-

ases in Arabidopsis and Drosophila are required for

viability. No reports on the mutating of the two putative

mammalian m6A methyltransferases, METTL3 and

METTL14, have been published. WTAP, one of the

other subunits of the methyltransferase complex, is

required for differentiation of endoderm and mesoderm

in the mouse embryo and the WTAP mutant embryos die

between day 6.5 and day 10.5 [50,51].

Obesity and type 2 diabetes obviously depends upon

environmental and social factors such as inactive daily

life and unhealthy diet. On the other hand, some genetic

variants clearly increase the risk of weight gain and in

2007 several genome wide association studies (GWAS)

identified an association with common variants of the

FTO gene and childhood and adult obesity [52–54]. While

variants of several genes have been found to increase

weight gain, the variant most strongly associated with

obesity is found in intron 1 of the FTO gene. Despite

extensive efforts, the possible role of the FTO protein

and m6A dynamics in obesity remains elusive. In con-

trast, loss-of-function mutation in the FTO gene is

responsible for a recessive lethal syndrome [55]. Charac-

teristics of affected individuals include postnatal growth

retardation, microcephaly, psychomotor delay, brain def-

icits and cardiac defects [55]. These findings point

toward an essential role of FTO and m6A dynamics for

normal development of the human brain and the cardi-

ovascular system.

In mice, loss of the FTO gene causes postnatal growth

retardation whereas FTO overexpression leads to

increased food intake and obesity [56,57]. Most studies

in mice have been done on gene-targeted mutants,

which might be less informative for obesity. Yet, it has

been shown that FTO demethylate specific mRNAs that

regulates the activity of dopaminergic midbrain circuitry

[58]. In another study, FTO was found to have a role in

cellular sensing of amino acids and it was proposed that

FTO might influence the body mass index by cellular

nutrient sensing [59]. In a most recent study on FTO,

however, obesity variants within the FTO gene are

reported to form long-range functional connections

with the homeobox gene IRX3 [60��]. IRX3 is located



downstream from FTO and is, together with FTO and

four other genes, within the 1.6 Mb region that if deleted

causes the fused toes (Ft) mutation [61]. The body

weight of IRX3 deficient mice is reduced by 25–30%

mostly through loss off fat mass and an increase in

metabolic rate. Additionally, it was previously shown

that obesity associated variants located in FTO introns

contain conserved noncoding sequences overlapping

with regulatory elements of transcription factors and

that irx3a knockdown in zebrafish suggests a direct role

of IRX3 for both obesity and type 2 diabetes [62]. These

studies indicate that the FTO protein itself is not linked

to obesity in humans.

Finally, in an exciting study, it is reported that m6A

mRNA methylation affects the mammalian circadian

clock and that specific inhibition of m6A methylation

cause an elongation of the circadian period [63��]. There

is considerable epidemiological evidence, although com-

plex, for an association of circadian disruption and human

diseases such as obesity, diabetes and cancer [64]. Thus,

mutant organisms of m6A writers and readers should be

characterized for possible circadian disruption and disease

association.

Conclusions and future prospectsDespite the recent focus on m6A and the identification of

its dynamic appearance, studies on m6A are still in their

infancy. The highly regulated and sequence specific meth-

ylation of adenosine in mRNA points to the important

regulatory roles of m6A. This speculation is further sub-

stantiated by the severe phenotype of organisms, including

mice, lacking the proteins required for m6A metabolism.

Future, and probably present, studies on dynamic RNA

modifications would have the following focuses.

� Only three proteins of the mammalian methyltrans-

ferase complex have been identified. Several other

proteins of the complex exist and should be identified

along with other proteins that might specifically

interact with m6A modifications and shed light on

the highly controlled and sequence specific methyla-

tion of mRNA.

� At present, a simple and truly single-nucleotide

resolution strategy for identifying m6A in the tran-

scriptome is missing. Improved methodology would

allow for detailed analysis of reversible m6A sites in

development and disease.

� The fundamental role of m6A during meiosis is

revealed, yet, the detailed understanding of m6A

dynamics during meiosis is completely lacking. Mature

eggs and sperm are very rare in animal models for m6A

demethylases and discourage further analysis. Single-

cell analysis on immature cells could provide insight

into the specific regulation of m6A in mammalian

meiosis.


� The structures of the writers and erasers of m6A, in a

complex with RNA substrate, are lacking despite

substantial efforts in several laboratories. Thus,

detailed information on the structure-function relation-

ship of the writers and readers of m6A should be

pursued.

� It is reasonable to speculate that other dynamic

modifications of RNA bases exist. Mutant organisms

lacking methyl transferases for protein-methylation,

DNA-methylation or RNA-methylation can generally

be characterized by identifying the missing methyl

group, and the methyl group can be added in vitro by

the addition of the recombinant enzyme. It is more

difficult to study the reversal of dynamic modifications

where a fine tuned balance might only be slightly

distorted, and thus, the characterization of demethy-

lases is lagging behind. The identification of reversible

modifications in short-lived RNA species is another

challenge. Nevertheless, future work should aim at

identifying other reversible modifications in RNA and

initially the focus could be on relatively stable and

abundant RNAs such as tRNAs and ribosomal RNAs.

AcknowledgementsWe acknowledge the generous support from the Norwegian ResearchCouncil, The Norwegian Cancer Society and Oslo University Hospital. Thisproject is also supported by the Norwegian-Polish collaborative grant.

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41. Chen W, Zhang L, Zheng G, Fu Y, Ji Q, Liu F, Chen H, He C: Crystalstructure of the RNA demethylase ALKBH5 from zebrafish.FEBS Lett 2014, 588:892-898.

42. Aik W, Scotti JS, Choi H, Gong L, Demetriades M, Schofield CJ,McDonough MA: Structure of human RNA N6-methyladeninedemethylase ALKBH5 provides insights into its mechanismsof nucleic acid recognition and demethylation. Nucleic AcidsRes 2014.

43.��

Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M,Dai Q, Jia G, Ren B, Pan T, He C: N6-methyladenosine-dependent regulation of messenger RNA stability. Nature 2014,505:117-120.

A ground breaking paper with the first identification of an m6A readerprotein.

44. Cook KB, Kazan H, Zuberi K, Morris Q, Hughes TR: RBPDB: adatabase of RNA-binding specificities. Nucleic Acids Res 2011,39:D301-D308.

45. Ray D, Kazan H, Cook KB, Weirauch MT, Najafabadi HS, Li X,Gueroussov S, Albu M, Zheng H, Yang A, Na H, Irimia M,Matzat LH, Dale RK, Smith SA, Yarosh CA, Kelly SM, Nabet B,Mecenas D, Li W, Laishram RS, Qiao M, Lipshitz HD, Piano F,Corbett AH, Carstens RP, Frey BJ, Anderson RA, Lynch KW,Penalva LO, Lei EP, Fraser AG, Blencowe BJ, Morris QD,Hughes TR: A compendium of RNA-binding motifs fordecoding gene regulation. Nature 2013, 499:172-177.

46. Niu Y, Zhao X, Wu YS, Li MM, Wang XJ, Yang YG: N6-methyl-adenosine (m6A) in RNA: an old modification with a novelepigenetic function. Genom Proteom Bioinform 2013, 11:8-17.

47. Clancy MJ, Shambaugh ME, Timpte CS, Bokar JA: Induction ofsporulation in Saccharomyces cerevisiae leads to theformation of N6-methyladenosine in mRNA: a potentialmechanism for the activity of the IME4 gene. Nucleic Acids Res2002, 30:4509-4518.

48. Zhong S, Li H, Bodi Z, Button J, Vespa L, Herzog M, Fray RG: MTAis an Arabidopsis messenger RNA adenosine methylase andinteracts with a homolog of a sex-specific splicing factor. PlantCell 2008, 20:1278-1288.

49. Hongay CF, Orr-Weaver TL: Drosophila Inducer of MEiosis 4(IME4) is required for Notch signaling during oogenesis. ProcNatl Acad Sci U S A 2011, 108:14855-14860.

50. Horiuchi K, Umetani M, Minami T, Okayama H, Takada S,Yamamoto M, Aburatani H, Reid PC, Housman DE, Hamakubo T,Kodama T: Wilms’ tumor 1-associating protein regulates G2/Mtransition through stabilization of cyclin A2 mRNA. Proc NatlAcad Sci U S A 2006, 103:17278-17283.

51. Fukusumi Y, Naruse C, Asano M: Wtap is required fordifferentiation of endoderm and mesoderm in the mouseembryo. Dev Dyn 2008, 237:618-629.

52. Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P,Carlsson LM, Kiess W, Vatin V, Lecoeur C, Delplanque J, Vaillant E,Pattou F, Ruiz J, Weill J, Levy-Marchal C, Horber F, Potoczna N,Hercberg S, Le SC, Bougneres P, Kovacs P, Marre M, Balkau B,Cauchi S, Chevre JC, Froguel P: Variation in FTO contributes tochildhood obesity and severe adult obesity. Nat Genet 2007,39:724-726.

53. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM,Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B,Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM,


Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y,Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ,Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M,Hitman GA, Palmer CN, Doney AS, Morris AD, Smith GD,Hattersley AT, McCarthy MI: A common variant in the FTO geneis associated with body mass index and predisposes tochildhood and adult obesity. Science 2007, 316:889-894.

54. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, Najjar S,Nagaraja R, Orru M, Usala G, Dei M, Lai S, Maschio A, Busonero F,Mulas A, Ehret GB, Fink AA, Weder AB, Cooper RS, Galan P,Chakravarti A, Schlessinger D, Cao A, Lakatta E, Abecasis GR:Genome-wide association scan shows genetic variants in theFTO gene are associated with obesity-related traits. PLoSGenet 2007, 3:e115.

55. Boissel S, Reish O, Proulx K, Kawagoe-Takaki H, Sedgwick B,Yeo GS, Meyre D, Golzio C, Molinari F, Kadhom N, Etchevers HC,Saudek V, Farooqi IS, Froguel P, Lindahl T, O’Rahilly S, Munnich A,Colleaux L: Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation andmultiple malformations. Am J Hum Genet 2009, 85:106-111.

56. Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Bruning JC,Ruther U: Inactivation of the Fto gene protects from obesity.Nature 2009, 458:894-898.

57. Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L,Wells S, Bruning JC, Nolan PM, Ashcroft FM, Cox RD:Overexpression of Fto leads to increased food intake andresults in obesity. Nat Genet 2010, 42:1086-1090.

58. Hess ME, Hess S, Meyer KD, Verhagen LA, Koch L, Bronneke HS,Dietrich MO, Jordan SD, Saletore Y, Elemento O, Belgardt BF,Franz T, Horvath TL, Ruther U, Jaffrey SR, Kloppenburg P,Bruning JC: The fat mass and obesity associated gene (Fto)regulates activity of the dopaminergic midbrain circuitry. NatNeurosci 2013, 16:1042-1048.

59. Gulati P, Cheung MK, Antrobus R, Church CD, Harding HP,Tung YC, Rimmington D, Ma M, Ron D, Lehner PJ, Ashcroft FM,Cox RD, Coll AP, O’Rahilly S, Yeo GS: Role for the obesity-related FTO gene in the cellular sensing of amino acids. ProcNatl Acad Sci U S A 2013, 110:2557-2562.

60.��

Smemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gomez-Marin C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF,Lee JH, Puviindran V, Tam D, Shen M, Son JE, Vakili NA, Sung HK,Naranjo S, Acemel RD, Manzanares M, Nagy A, Cox NJ, Hui CC,Gomez-Skarmeta JL, Nobrega MA: Obesity-associated variantswithin FTO form long-range functional connections with IRX3.Nature 2014, 507:371-375.

This study identifies a long-range connection of FTO-obesity variants withIRX3 and question a direct role for the FTO protein in obesity.

61. Peters T, Ausmeier K, Dildrop R, Ruther U: The mouse Fusedtoes (Ft) mutation is the result of a 1.6-Mb deletion includingthe entire Iroquois B gene cluster. Mamm Genome 2002,13:186-188.

62. Ragvin A, Moro E, Fredman D, Navratilova P, Drivenes O,Engstrom PG, Alonso ME, de la Calle ME, Gomez Skarmeta JL,Tavares MJ, Casares F, Manzanares M, van H, Molven V,Njolstad A, Argenton PR, Lenhard F, Becker TS: B: Long-rangegene regulation links genomic type 2 diabetes and obesity riskregions to HHEX, SOX4, and IRX3. Proc Natl Acad Sci U S A2010, 107:775-780.

63.��

Fustin JM, Doi M, Yamaguchi Y, Hida H, Nishimura S, Yoshida M,Isagawa T, Morioka MS, Kakeya H, Manabe I, Okamura H: RNA-methylation-dependent RNA processing controls the speed ofthe circadian clock. Cell 2013, 155:793-806.

This report shows that the period of the circadian clock is inverselyproportional to the methylation potential and that METTL3 knockdownresults in circadian period elongation.

64. Zelinski EL, Deibel SH, McDonald RJ: The trouble with circadianclock dysfunction: multiple deleterious effects on the brainand body. Neurosci Biobehav Rev 2014, 40:80-101.































































































































dynamic rna modifications in disease

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