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protein arginine methyltransferases ( prmts ) comprise a group of enzymes that catalyze the transfer of methyl groups to the amino acid arginine or the arginine residues of proteins in eukaryotic species . in mammals ,
nine isoforms have been identified to date that can be subdivided into three major types : i , ii , and iii . while all three types of prmts are capable of catalyzing monomethylation of arginine residues , type i prmts can transfer a second methyl group to the monomethylated nitrogen atom of the guanidino group of monomethyl arginine , resulting in the formation of proteins containing one or more asymmetric dimethylarginine residues .
type ii prmts transfer a methyl group to the unmodified nitrogen atom of the guanidine group of monomethyl arginine to form proteins with symmetric dimethylarginine residues .
type i prmts comprise prmt1 , prmt3 , prmt4 , prmt6 , and prmt8 and have been shown to function as transcriptional activators . in earlier reports
, prmts promoted active transcription of target genes by mediating asymmetric dimethylation of arginine residues on histones , resulting in increased acetylation and the subsequent activation of transcription .
examples include arginine 3 methylation on histone h4 ( h4r3 ) by prmt1 and arginine 17 and 26 methylation on histone h3 ( h3r17 and h3r26 ) by prmt4 .
more recent reports suggest that prmts can affect transcription by direct modification of transcriptional regulators .
type ii prmts ( prmt5 , prmt7 , and prmt9 ) are less well characterized and may function as transcriptional repressors , although some reports suggest that they can function as activators of transcription .
prmt5 , a predominant type ii prmt in mammals , represses transcription by promoting symmetric dimethylation of arginine 8 on histone h3 ( h3r8 ) and symmetric dimethylation of arginine 3 on histone h4 ( h4r3 ) .
the role of type iii prmts in the control of transcription has not been well characterized to date .
interestingly , recent reports suggest that prmts function as regulators of fuel metabolism through interaction with a number of transcriptional regulators in the pathway . in this review , we summarize recent findings regarding the roles of prmt isoforms in the control of fuel metabolism , with emphasis on glucose metabolism . we restrict our discussions to four widely studied isoforms : prmt1 , prmt4 , prmt5 , and prmt6 .
it is expressed ubiquitously in most tissues and may account for up to 85% of all prmt activity in the cell depending on experimental conditions .
in addition , it can also function as a coactivator of transcription factors by direct modification of arginine residues on the transcription factors themselves .
for example , prmt1-dependent methylation of runx1 is essential for its dissociation from msin3a , resulting in transcription .
foxo1 is a transcription factor containing a forkhead box domain that is conserved in various eukaryotic species .
it is involved in the control of signaling pathways in cellular stress resistance , longevity , apoptosis , and metabolism .
normally , foxo1 is present in the nucleus and functions as a transcriptional activator in the absence of growth factors or insulin . in the presence of such signals , three major serine / threonine residues ( thr24 , ser253 , and ser316 in mus muculus ) are phosphorylated by akt or its related agc kinases , resulting in an association with 14 - 3 - 3 , nuclear exclusion , ubiquitination , and subsequent degradation by a proteasome - dependent pathway .
a recent study found that prmt1 can also modulate foxo1 activity by controlling its nuclear localization . in the presence of oxidative stress ,
prmt1 promotes asymmetric dimethylation of foxo1 at arginines 248 and 250 , thereby inhibiting phosphorylation of the adjacent serine 253 , increasing its nuclear retention and promoting cell survival .
thus , prmt1 may function as a transcriptional co - activator for foxo1-dependent transcriptional events .
foxo1 has been shown to be a major transcriptional activator for genes involved in hepatic gluconeogenesis .
foxo1 binding sites , termed insulin response elements , have been mapped to a number of genes in the pathway , including the genes encoding phosphoenolpyruvate carboxykinase ( pepck ) , glucose 6-phosphatase ( g6pase ) , and peroxisome proliferator - activated receptor  co - activator 1 ( pgc-1 ) .
furthermore , transgenic expression of foxo1 in the liver increased gluconeogenesis , while liver - specific depletion of foxo1 in mice reduced glucose production in vivo , illustrating the critical role of this factor in hepatic gluconeogenesis .
prmt1 was shown to modulate asymmetric dimethylation of foxo1 at arginines 248 and 250 in the mouse liver , disturbing the ability of insulin to reduce glucose production in the liver .
overexpression of prmt1 promotes increased glucose production by hepatocytes , while acute depletion of prmt1 in mice reduces hepatic gluconeogenesis by promoting increased phosphorylation of foxo1 at serine 253 , leading to the decreased expression of foxo1 target genes during gluconeogenesis in mice .
however , the precise role of prmt1 in the control of foxo1-dependent gluconeogenesis should be further delineated by using liver - specific prmt1 knockout mice .
in addition , further study is necessary to determine the mechanism underlying the control of prmt1 activity in response to fasting or insulin resistance in the liver .
clarification regarding whether prmt1 is also involved in the general control of posttranscriptional modification would be of interest .
prmt4 , also known as coactivator - associated arginine methyltransferase 1 , is widely known as a coactivator for various nuclear hormone receptors , including androgen receptor , estrogen receptor , and thyroid hormone receptor .
it also exerts coactivator effects by interacting with other coactivators , including camp response element - binding protein ( creb ) binding protein ( cbp ) , p300/cbp - associated factor , steroid receptor coactivator-1 ( src-1 ) , and prmt1 , affecting their activity by direct methylation of their arginine residues in some cases or by modulating the arginine residues of histone h3 ( h3r17 and h3r26 ) .
prmt4 can function as an activator of myogenesis by acting as a coactivator of myocyte - specific enhancer factor 2c , nuclear receptor coactivator 3 . as a coactivator for nuclear factor-b
, prmt4 plays a role as a coactivator of ppar- , promoting fat cell differentiation .
interestingly , aberrant expression of prmt4 was detected in prostate carcinoma , indicating the potential importance of this factor in normal signaling cascades in prostate cells .
in addition , prmt4 may also be involved in the control of mrna stability by methylation of hur , an mrna - stabilizing protein .
creb plays a key role in the control of hepatic gluconeogenesis . under fasting conditions ,
the pancreatic hormone glucagon activates camp signals in hepatocytes and activates protein kinase a ( pka ) .
pka promotes hepatic gluconeogenesis at the transcription level by promoting phosphorylation of creb at serine 133 .
this in turn is crucial for recruiting coactivators such as cbp and p300 , leading to the activation of target genes such as pepck , g6pase , and pgc-1. indeed , liver - specific expression of a - creb , a creb inhibitor , or sirna targeting creb lowered blood glucose levels , a response associated with reduced gluconeogenic gene expression .
a recent report suggested that prmt4 controls hepatic gluconeogenesis by interacting with creb in hepatocytes .
krones - herzig and colleague   showed that prmt4 can associate physically with creb on the promoters of its target genes , such as the pepck and g6pase promoters .
this promotes increased histone h3 acetylation by cbp / p300 , leading to the increased transcription of creb target genes .
this report , however , was somewhat contradictory to a previous report showing that prmt4 turns off creb - dependent transcription by selective arginine methylation in the kix domain of cbp , a creb - interacting domain , to dissociate it from creb .
further analysis is necessary to delineate the relative contributions of arginine methylation in cbp and histone h3 to creb - dependent transcription .
prmt5 is a type ii prmt that promotes symmetric dimethylation of arginine residues in substrates .
normally , symmetric dimethylation of arginine in histones is regarded as a marker for transcriptional inhibition . prmt5
interacts with various transcriptional regulators , including brahma - related gene-1 , blimp1 , and snail , and promotes symmetric dimethylation of arginine residues in histones ( h3r8 and h4r3 ) .
prmt5 was also shown to function as a transcriptional co - activator in myod - dependent regulation of myog transcription in muscle tissues .
recently , tsai and colleague   reported that prmt5 can function as a coactivator of creb - dependent transcriptional events in the liver .
prmt5 was shown to specifically interact with crtc2 , a creb coactivator that enhances creb - dependent gluconeogenic programs under fasting conditions .
recruitment of prmt5 to the promoters of pepck and g6pase in turn promotes increased symmetric dimethylation of histone h3 at arginine 2 ( h3r2 ) , leading to increased lysine modification of the same histones by wd repeat - containing protein 5 ( wdr5)-containing lysine methyl transferase complexes .
tsai and colleague   suggested that enhanced chromatin accessibility following h3r2 methylation is critical for stimulating creb phosphorylation and subsequent transcription .
interestingly , a recent report suggested that prmt5 can potentiate the repressor activity of small heterodimer partner ( shp ) , a known repressor of gluconeogenesis , by direct methylation of this protein at arginine 57 .
methylated shp in turn recruits transcriptional corepressors , including brm , sin3a , and hdac1 , leading to the inhibition of metabolic target genes .
prmt5-dependent regulation of shp is essential for reducing bile acid and hepatic triglyceride levels and improving glucose tolerance in this model .
whether prmt5-dependent regulation of creb - dependent transcription can be compromised by prmt5-mediated activation of shp in animal models requires further study .
, prmt6 was shown to contribute to transcriptional repression by enhancing asymmetric dimethylation of histone 3 at arginine 2 ( h3r2 ) , which in turn blocks wdr5-dependent h3k4 methylation and reduces transcription .
on the other hand , prmt6 was also shown to promote asymmetric dimethylation of histone h4 at arginine 3 ( h4r3 ) , a marker for transcriptional activation , suggesting that it can also function as a coactivator of transcription .
indeed , prmt6 was shown to enhance the transcriptional activity of multiple nuclear hormone receptors in association with other coactivators including src-1 .
we recently showed that prmt6 can also regulate hepatic gluconeogenesis via activation of a crtc2-dependent transcriptional pathway in the liver .
we showed that prmt6 directly modulates asymmetric dimethylation of multiple arginine residues in the n - terminus of ctrc2 , thereby potentiating the interaction between crtc2 and creb on the promoters of gluconeogenic genes .
liver prmt6 expression was increased in obese and insulin - resistant mice , and depletion of prmt6 restored normal glycemia in these mouse models .
this underscores the importance of prmt6 in the control of crtc2-dependent gluconeogenic transcription in vivo .
we also observed similar modification of arginine residues in other crtc proteins by prmt6 , suggesting that prmt6-dependent regulation of crtc activity can also affect other aspects of metabolism in cells such as fat cells or pancreatic -cells .
in this review , we have summarized recent findings regarding the roles of prmts in the control of hepatic glucose metabolism .
interestingly , except for prmt1 , which regulates foxo1 , all of the prmts known to be involved in the control of hepatic glucose metabolism ( prmt4 , prmt5 , and prmt6 ) affect the transcriptional activity of creb - crtc2-dependent machinery ( fig .
1 ) . it will be of great interest to delineate the relative contribution of each prmt protein to the control of hepatic gluconeogenesis in vivo .
glucose homeostasis is tightly controlled by the regulation of glucose production in the liver and glucose uptake into peripheral tissues , such as skeletal muscle and adipose tissue . under prolonged fasting 
 , hepatic gluconeogenesis is mainly responsible for glucose production in the liver , which is essential for tissues , organs , and cells , such as skeletal muscle , the brain , and red blood cells . 
 hepatic gluconeogenesis is controlled in part by the concerted actions of transcriptional regulators . 
 fasting signals are relayed by various intracellular enzymes , such as kinases , phosphatases , acetyltransferases , and deacetylases , which affect the transcriptional activity of transcription factors and transcriptional coactivators for gluconeogenic genes . 
 protein arginine methyltransferases ( prmts ) were recently added to the list of enzymes that are critical for regulating transcription in hepatic gluconeogenesis . in this review , 
 we briefly discuss general aspects of prmts in the control of transcription . 
 more specifically , we summarize the roles of four prmts : prmt1 , prmt 4 , prmt 5 , and prmt 6 , in the control of hepatic gluconeogenesis through specific regulation of foxo1- and creb - dependent transcriptional events .