Reply:

Abstract

As Xu etal. stated,1 the previous study by Krones-Herzig etal. clearly demonstrated the functional significance of protein arginine methyltransferase-4 [PRMT4; also known as coactivator-associated arginine methyltransferase-1 (CARM-1)]-dependent regulation of hepatic glucose production in cultured hepatocytes.2 Specifically, they showed that PRMT4 was recruited to the cyclic adenosine monophosphate (cAMP) response element of promoters of both phosphoenol pyruvate carboxykinase (PEPCK) and glucose 6-phosphatase catalytic subunit (G6Pase), which resulted in the increased methylation of arginine 17 on histone H3 and acetylation of histone H4. These results indicated that cAMP response element-binding protein (CREB) might recruit PRMT4 and other known histone acetyltransferases, such as CREB-binding protein (CBP)/p300, onto the promoters of gluconeogenic genes. Indeed, phosphorylation of serine 133 of CREB by cAMP-dependent protein kinase is a key mechanism for the recruitment of CBP/p300 and subsequent activation of CREB-target gene transcription.3 Although we showed that protein arginine methyltransferase-1 (PRMT1) is critical in activating FoxO1-dependent gluconeogenesis by promoting arginine methylation of FoxO1,4 we failed to detect any PRMT1-dependent increase in arginine methylation of histone H3 or H4, at least using the adenovirus-mediated overexpression system in hepatocytes (data not shown). Indeed, we suspect that FoxO1-dependent transcriptional activation might be quite a bit more complicated, because CBP/p300, a potent histone acetyltransferase that normally activates transcription factors, was shown to be involved in the direct acetylation/inhibition of FoxO1.5 Furthermore, recent studies also indicated that histone deacetylase 3 was recruited onto the FoxO1-binding sites of both PEPCK and G6Pase in primary hepatocytes,6 suggesting that certain regions of gluconeogenic promoters might be potentially hypoacetylated. Currently, we are in the process of generating liver-specific knockout mice for PRMT1 to directly address this issue. Further studies utilizing this mouse model will be helpful to decipher the complex histone codes in the regulation of hepatic gluconeogenic gene expression. Dahee Choi B.S.*, Kyoung-Jin Oh Ph.D.*, Seung-Hoi Koo Ph.D.*, * Division of Biochemistry and Molecular Biology, Department of Molecular Cell Biology and Samsung Biomedical Institute, Sungkyunkwan University School of Medicine, Suwon, Korea.