T-cell factor 4 and β-catenin chromatin occupancies pattern zonal liver metabolism in mice

Abstract

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

Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells

“…While there are a few reports on the differential activity of the HNF4␣ isoforms (22,(93)(94)(95), to our knowledge, this is the first in-depth functional comparison of the HNF4␣ isoforms in a colon cancer line. Likewise, while there are reports of interactions between HNF4␣ and TCF4 (12,31,(40)(41)(42)(43)(44)(45), this is the first report to examine the effect of the presence of the HNF4␣ isoforms on TCF4 chromatin binding, identify a potential three-way interaction between HNF4␣, TCF4, and AP-1, and examine in great depth the DNA binding specificity of the HNF4␣ isoforms and TCF4.…”

“…All told, there were many more genes with HNF4␣ ChIP-seq peaks than were dysregulated in the RNA-seq. While this is not uncommon in genomics analysis (40), a lower cutoff (1.2-fold) and a greater distance between the peak and the putative target gene showed more overlap (not shown); a longer induction time (Ͼ24 h of DOX) also would have presumably increased the number of dysregulated genes without significantly altering the HNF4␣ peaks. (See Tables S5 and S6 in the supplemental material for a list of genes bound by HNF4␣.…”

“…There are an increasing number of reports that indicate a potential cross talk between HNF4␣ and the Wnt pathway in liver zonation, hepatocellular carcinoma (HCC) development, and colorectal cancer: Physical interactions between HNF4␣ and TCF4 have been reported in soluble nuclear extracts (NE) as well as in chromatin-bound fractions on isolated promoters (12,(39)(40)(41)(42). LEF1/TCF binding motifs have also been found enriched in HNF4␣ chromatin immunoprecipitation sequencing (ChIP-seq) peaks and vice versa (40,(42)(43)(44)(45), suggesting a potential coregulation by these two transcription factors (TFs). The nature of that coregulation, however,…”

The WNT/β-Catenin Pathway Is a Transcriptional Regulator of CYP2E1,CYP1A2, and Aryl Hydrocarbon Receptor Gene Expression in Primary Human Hepatocytes

“…Indeed, direct binding of TCF4 (coactivator for b-catenin) on the 5000-bp region spanning the CYP2E1 promoter could not be demonstrated (Liu et al, 2012). Recently, using Chip-seq analysis, Gougelet et al (2014) identified a WRE motif in a 100-kpb region in the upstream and intragenic regions of mouse Cyp2e1 but did not demonstrate its functionality. An indirect effect via HNF1a transcriptional activity was also proposed .…”

Correlation of the TCF7L2 (rs7903146) polymorphism with an enhanced risk of type 2 diabetes mellitus: a meta-analysis

“…Loos et al (2007) demonstrated that TCF7L2 polymorphisms increase the risk of T2DM by impairing β-cell function and modulating proinsulin levels in a British Europid population. TCFL2 encodes a basic helix-loop-helix transcription factor 4 (TCF-4), which acts as a nuclear receptor for the Wnt/β-catenin pathway (Smith, 2007), and can preferentially bind to Wnt-responsive elements in genes induced by β-catenin (Gougelet et al, 2014). It is well known that the β-catenin/TCF-4 complex participates in various biological events.…”