Wtap-flox Mouse

WTAP, short for Wilms tumor 1-associated protein, is a key regulatory subunit of the RNA N6-methyladenosine (m6A) methyltransferase complex. The m6A modification, which WTAP is involved in, regulates multiple biological processes such as RNA splicing, cell proliferation, cell cycle, and embryonic development [2,5,6]. It exerts its m6A modification function by binding to methyltransferase-like 3 (METTL3) in the nucleus to form the METTL3-methyltransferase-like 14 (METTL14)-WTAP (MMW) complex, localizing to nuclear patches [5].

In various disease models, WTAP shows distinct effects. In hepatocellular carcinoma (HCC), WTAP is highly expressed, promoting cell proliferation and tumor growth both in vitro and in vivo. It epigenetically silences ETS1 through m6A-HuR-dependent mechanisms, and modulation of the G2/M phase of HCC cells occurs via a p21/p27-dependent pattern mediated by ETS1 [1]. In diabetic nephropathy, WTAP promotes the m6A methylation of NLRP3 mRNA, upregulating NLRP3 inflammasome activation, cell pyroptosis, and inflammation [3]. Hepatic deletion of Wtap in mice leads to non-alcoholic steatohepatitis (NASH) due to increased lipolysis in white adipose tissue, enhanced hepatic free fatty acids uptake, and induced inflammation, mediated by IGFBP1, CD36, and cytochemokines such as CCL2 respectively [4].

In conclusion, WTAP is crucial in regulating m6A-mediated RNA metabolism, which impacts various biological processes. Its role in disease development, as demonstrated by gene knockout (KO) or conditional knockout (CKO) mouse models in areas like cancer, diabetic nephropathy, and NASH, provides potential therapeutic targets. Understanding WTAP's functions helps in unravelling the molecular mechanisms of these diseases and developing novel treatment strategies.