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3
Topology of 6-methyladenosine (m6A) in mRNA
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 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.
9
Mutant organisms and disease
It was report that 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. 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.
8
hm6A
FTO
f6A
have been identified in vivo
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. In contrast, the role of FTO in demethylating 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
Dynamic RNA modifications in disease
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.
4
More recently, a high-resolution map of m6A modifications in meiotic yeast transcripts was obtained .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. Currently, several protocols are being developed for the identification of m6A in the transcriptome.
2
Introduction
Methylations of mammalian 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
10
A few reports writed ,loss-of-function mutation in the FTO gene is responsible for a recessive lethal syndrome . Characteristics of affected individuals include postnatal growth retardation, microcephaly, psychomotor delay, brain def-icits and cardiac defects . These findings point toward an essential role of FTO and m6A dynamics for normal development of the human brain and the cardi- ovascular system.
7
FTO proten METTL3
catalyzes
m6A
overlapping functions downregulation
METTL14
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
12
Finally, in an exciting study, it is reported that m6A mRNA methylation affects the mammalian circadian clock and that sp百度文库cific inhibition of m6A methylation cause an elongation of the circadian period. There is considerable epidemiological evidence, although complex, for an association of circadian disruption and human diseases such as obesity, diabetes and cancer . Thus, mutant organisms of m6A writers and readers should be characterized for possible circadian disruption and disease association.
13
Conclusions and future prospects
Despite the recent focus on m6A and the identification of its dynamic appearance, studies on m6A are still in their infancy. Future, and probably present, studies on dynamic RNA modifications would have the following focuses.
5
6
Writers and erasers of 6-methyladenosine(m6A) in mRNA The 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 component of this complex. Recently, affinity purification of taggedMETTL3 led to the identification of METTL14, thus suggesting that the methyltransferase complex contains two active methyltransferase subunits.
11
loss of the FTO gene
postnatal growth retardation increased food intake and obesity
In mice
overexpression
It has been shown that FTO demethylate specific mRNAs that regulates the activity of dopaminergic midbrain circuitry. 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.
Topology of 6-methyladenosine (m6A) in mRNA
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 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.
9
Mutant organisms and disease
It was report that 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. 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.
8
hm6A
FTO
f6A
have been identified in vivo
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. In contrast, the role of FTO in demethylating 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
Dynamic RNA modifications in disease
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.
4
More recently, a high-resolution map of m6A modifications in meiotic yeast transcripts was obtained .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. Currently, several protocols are being developed for the identification of m6A in the transcriptome.
2
Introduction
Methylations of mammalian 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
10
A few reports writed ,loss-of-function mutation in the FTO gene is responsible for a recessive lethal syndrome . Characteristics of affected individuals include postnatal growth retardation, microcephaly, psychomotor delay, brain def-icits and cardiac defects . These findings point toward an essential role of FTO and m6A dynamics for normal development of the human brain and the cardi- ovascular system.
7
FTO proten METTL3
catalyzes
m6A
overlapping functions downregulation
METTL14
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
12
Finally, in an exciting study, it is reported that m6A mRNA methylation affects the mammalian circadian clock and that sp百度文库cific inhibition of m6A methylation cause an elongation of the circadian period. There is considerable epidemiological evidence, although complex, for an association of circadian disruption and human diseases such as obesity, diabetes and cancer . Thus, mutant organisms of m6A writers and readers should be characterized for possible circadian disruption and disease association.
13
Conclusions and future prospects
Despite the recent focus on m6A and the identification of its dynamic appearance, studies on m6A are still in their infancy. Future, and probably present, studies on dynamic RNA modifications would have the following focuses.
5
6
Writers and erasers of 6-methyladenosine(m6A) in mRNA The 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 component of this complex. Recently, affinity purification of taggedMETTL3 led to the identification of METTL14, thus suggesting that the methyltransferase complex contains two active methyltransferase subunits.
11
loss of the FTO gene
postnatal growth retardation increased food intake and obesity
In mice
overexpression
It has been shown that FTO demethylate specific mRNAs that regulates the activity of dopaminergic midbrain circuitry. 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.