b-catenin signaling can be both a physiological and oncogenic pathway in the liver. It controls compartmentalized gene expression, allowing the liver to ensure its essential metabolic function. It is activated by mutations in 20%-40% of hepatocellular carcinomas (HCCs) with specific metabolic features. We decipher the molecular determinants of b-catenindependent zonal transcription using mice with b-catenin-activated or -inactivated hepatocytes, characterizing in vivo their chromatin occupancy by T-cell factor (Tcf )24 and b-catenin, transcriptome, and metabolome. We find that Tcf-4 DNA bindings depend on bcatenin. Tcf-4/b-catenin binds Wnt-responsive elements preferentially around b-catenininduced genes. In contrast, genes repressed by b-catenin bind Tcf-4 on hepatocyte nuclear factor 4 (Hnf-4)-responsive elements. b-Catenin, Tcf-4, and Hnf-4a interact, dictating bcatenin transcription, which is antagonistic to that elicited by Hnf-4a. Finally, we find the drug/bile metabolism pathway to be the one most heavily targeted by b-catenin, partly through xenobiotic nuclear receptors. Conclusions: b-catenin patterns the zonal liver together with Tcf-4, Hnf-4a, and xenobiotic nuclear receptors. This network represses lipid metabolism and exacerbates glutamine, drug, and bile metabolism, mirroring HCCs with b-catenin mutational activation. (HEPATOLOGY 2014;59:2344-2357 See Editorial on Page 2080 T he adult liver is a quiescent organ, fully compartmentalized to accomplish its crucial metabolic role. Its vasculature gives rise to two distinct hepatocyte populations: one located in the vicinity of the portal vein and the other around the central vein. 1 Pericentral (PC) hepatocyte metabolism is complementary to that of periportal (PP) hepatocytes in terms of energy, ammonia, and xenobiotic metabolism. This complementarity arises as a result of the production of distinct specialized proteins in the two zones. 1,2 It has been demonstrated that the Wnt/b-catenin pathway is the master transcriptional regulator of this zonal metabolism, and that control is rendered by a Wnt morphogenetic concentration gradient high in PC hepatocytes and decreasing toward PP hepatocytes. 3,4

Antisense oligonucleotides (ASOs) represent a new and highly promising class of drugs for personalized medicine. In the last decade, major chemical developments and improvements of the backbone structure of ASOs have transformed them into true approved and commercialized drugs. ASOs target both DNA and RNA, including pre-mRNA, mRNA, and ncRDA, based on sequence complementary. They are designed to be specific for each identified molecular and genetic alteration to restore a normal, physiological situation. Thus, the characterization of the underpinning mechanisms and alterations that sustain pathology is critical for accurate ASO-design. ASOs can be used to cure both rare and common diseases, such as orphan genetic alterations and cancer. Through pioneering examples, this review shows the versatility of the mechanisms of action that provide ASOs with the potential capacity to achieve custom treatment, revolutionizing personalized medicine.