Transcription factor GATA6: a novel marker and putative inducer of ductal metaplasia in biliary atresia

Abstract

Biliary atresia (BA), a neonatal liver disease, is characterized by obstruction of extrahepatic bile ducts with subsequent cholestasis, inflammation, and progressive liver fibrosis. To gain insights into the pathophysiology of BA, we focused attention on GATA6, a transcription factor implicated in biliary development. Early in fetal development GATA6 expression is evident in cholangiocytes and hepatocytes, but by late gestation it is extinguished in hepatocytes. Utilizing a unique set of BA liver samples collected before and after successful portoenterostomy (PE), we found that GATA6 expression is markedly upregulated in hepatocytes of patients with BA compared with healthy and cholestatic disease controls. This upregulation is recapitulated in two murine models simulating bile duct obstruction and intrahepatic bile ductule expansion. GATA6 expression in BA livers correlates with two established negative prognostic indicators (age at PE, degree of intrahepatic bile ductule expansion) and decreases after normalization of serum bilirubin by PE. GATA6 expression in BA livers correlates with expression of known regulators of cholangiocyte differentiation ( JAGGED1, HNF1β, and HNF6). These same genes are upregulated after enforced expression of GATA6 in human hepatocyte cell models. In conclusion, GATA6 is a novel marker and a putative driver of hepatocyte-cholangiocyte metaplasia in BA, and its expression in hepatocytes is downregulated after successful PE. NEW & NOTEWORTHY A pathological hallmark in the liver of patients with biliary atresia is ductular reaction, an expansion of new bile ductules that are thought to arise from conversion of mature hepatocytes. Here, we show that transcription factor GATA6 is a marker and potential driver of hepatocyte ductal metaplasia in biliary atresia. Hepatocyte GATA6 expression is elevated in biliary atresia, correlates with bile duct expansion, and decreases after successful portoenterostomy.

Biliary atresia: a scientometric analysis of the global research architecture and scientific developments

“…Still, many countries, including the USA and France maintain a decentralized care policy . Nevertheless, there is a strategic drift towards concentration of resources – both in the clinical and research spheres – that recognizes the limitations of trying to treat an uncommon disease in single centers . As a result, several national and international BA research consortiums and registries have been set up to foster scientific progress with this rare condition (Table ).…”

Epigenomic signatures in liver and blood of Wilson disease patients include hypermethylation of liver-specific enhancers

“…Differentially methylated genes identified in patient livers significantly overlapped with those in tx-j fetal liver and included several genes encoding transcription factors important in liver development. GATA6 is involved in multiple stages of liver maturation and highly expressed in hepatocytes during early fetal development [23]. FOXA1 is crucial in initiating specification during liver embryogenesis [24] and is also expressed in adult livers, whereas VTN , a FOXA1 target gene, is involved in embryonic stem cell maturation [25] and has been shown to be upregulated in fetal hepatic stellate cells [26].…”

Transcription factor GATA4 associates with mesenchymal-like gene expression in human hepatoblastoma cells

“…For microarray data, background correction was done on raw array data using BeadStudio software (Illumina) before quantile normalization and log 2 transformation were performed using the BeadArray Bioconductor package. 15 Differentially expressed genes (14) 100 (24) were identified using linear models for microarray data (LIMMA) 16 with Benjamini-Hochberg correction. The expression level changes with a false discovery rate (FDR) below 5% were considered as significantly differentially expressed.…”