To the Editors:

In a recent report, Choi et al.1 demonstrated that protein arginine methyltransferase-1 (PRMT1)-dependent arginine modification of FoxO1 contributed to the regulation of hepatic glucose production in a mouse model. However, despite presenting the finding of the FoxO1 protein, the investigators failed to discuss another well-defined class of PRMT1 substrates: histones, methylations of which have been identified as key “histone codes” in epigenetic regulation2 and have been shown to regulate hepatic gluconeogenesis under the control of another PRMT in a previous study by Krones-Herzig et al.3 Herein, we compare the two similar studies and suggest that PRMT1-mediated histone arginine methylation should be involved in the network of hepatic glucose metabolism regulation.

Both groups found that the PRMTs regulated the same target genes, but methylated different proteins (Table 1). Herzig et al. suggested that PRMT4 contributed to the regulation of hepatic glucose metabolism by methylating histone H3, because methylations of H3 arginines are known to be transcriptional activation markers.4 Based on these findings, we hypothesize that the function of PRMT1 in the regulation of hepatic glucose production may also be mediated by the methylation of histones, because PRMT1 is known to methylate histone H4 at arginine 3, generating the H4R3me2a marker, thus contributing to the histone codes as a transcriptional activation marker, similarly to PRMT4.5 Furthermore, as transcriptional coactivators, both PRMT1 and PRMT4 are often recruited to promoters by a number of different transcription factors.2 Because PRMT4 has been reported to enhance nuclear factor kappa light-chain enhancer of activated B cells–mediated gene transcription by methylation of histone H3,6 it is reasonable to presume that PRMT1 also enhances FoxO1-mediated gene transcription through the methylation of histone H4, which may be another unrevealed mechanism of hepatic glucose production regulation. Further studies on PRMT1-mediated histone methylation may advance our understanding of the role of histone codes in hepatic gene regulation. Thus, the current findings of Choi et al. are expected to have profound significance.

Table 1. Role of PRMT Family Members in the Regulation of Hepatic Glucose Production
 Choi et al.1Krones-Herzig et al.3
  1. Abbreviations: PRMT, protein arginine methyltransferase; CARM1, coactivator-associated arginine methyltransferase 1; cAMP,, cyclic adenosine monophosphate; PKA, protein kinase A; CREB, cAMP response element-binding factor; PEPCK, phosphoenol pyruvate carboxykinase; G6Pase, glucose 6-phosphatase catalytic subunit.

PRMT family memberPRMT1PRMT4 (CARM1)
Signal pathwayAkt1 pathwaycAMP/PKA pathway
Models in vitroMouse primary hepatocytesHuman HepG2 hepatocytes Rat H4IIE hepatocytes
Models in vivoC57BL/6 mice db/db miceAbsence
Interacted proteinsFoxO1CREB
Methylated proteinsFoxO1Histone H3
Target genesPEPCK, G6PasePEPCK, G6Pase


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  • 1
    Choi D, Oh KJ, Han HS, Yoon YS, Jung CY, Kim ST, Koo SH. Protein arginine methyltransferase-1 regulates hepatic glucose production in a FoxO1 dependent manner. Hepatology 2012 Apr 24. doi: 10.1002/hep.25809.
  • 2
    Bedford MT, Richard S. Arginine methylation an emerging regulator of protein function. Mol Cell 2005; 18: 263-272.
  • 3
    Krones-Herzig A, Mesaros A, Metzger D, Ziegler A, Lemke U, Bruning JC, Herzig S. Signal-dependent control of gluconeogenic key enzyme genes through coactivator-associated arginine methyltransferase 1. J Biol Chem 2006; 281: 3025-3029.
  • 4
    Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, et al. Regulation of transcription by a protein methyltransferase. Science 1999; 284: 2174-2177.
  • 5
    Wang H, Huang ZQ, Xia L, Feng Q, Erdjument-Bromage H, Strahl BD, et al. Methylation of histone H4 at arginine 3 facilitating transcriptional activation by nuclear hormone receptor. Science 2001; 293: 853-857.
  • 6
    Miao F, Li S, Chavez V, Lanting L, Natarajan R. Coactivator-associated arginine methyltransferase-1 enhances nuclear factor-kappaB-mediated gene transcription through methylation of histone H3 at arginine 17. Mol Endocrinol 2006; 20: 1562-1573.

Zhenyu Xu*, Yue Wang*, Houqi Liu*, * Research Center of Developmental Biology, Second Military Medical University, Shanghai, China.