Transcriptional control in the mammalian liver: liver development, perinatal repression, and zonal gene regulation

Abstract

Liver function is crucial for maintaining metabolic homeostasis in mammals. Numerous genes must be properly regulated for the liver to develop and perform a variety of activities. Several recent gene-knockout studies in mice have clarified the roles of GATA6, HNF4alpha, and Foxa1/Foxa2 in early stages of liver formation. After the liver forms, transcriptional changes continue to occur; during the perinatal period, certain genes such as alpha-fetoprotein and H19 are silenced, others are activated, and position-dependent (or zonal) regulation is established. Zhx2 was recently identified as one factor involved in postnatal repression of alpha-fetoprotein and other genes. Furthermore, several studies indicate that negative regulation is involved in the zonal control of glutamine synthetase. Finally, exciting new evidence indicates that signaling through the Wnt/beta-catenin pathway is also involved in zonal regulation in the adult liver.

Regulation of hepatocyte identity and quiescence

“…The mechanisms involved in the postnatal repression of fetal genes are not completely known. The zinc finger and homeoboxes factor 2 (ZHX2), whose expression is higher in the adult liver than in fetal liver, has been shown to inhibit the postnatal expression of AFP, glypican-3 and H19 in mice [91,92]. Interestingly, expression of ZHX2 is reduced in HCC cells and tissues, and low ZHX2 levels were mechanistically linked to the upregulation of glypican-3 expression and tumor growth [93,94].…”

Transcriptional Control of Hepatocyte Differentiation

“…Nevertheless, the reason for AFP repression is unknown, since persistent expression has no detrimental effects. Three other genes share the oncofetal expression pattern -Glypican 3 (GPC3), the microRNA precursor H19, and lipoprotein lipase [142][143][144]. They have limited developmental or oncogenic activity, and recent global studies of gene expression have not significantly enlarged the set of oncofetal proteins in liver.…”

“…BALB/cJ is therefore a naturally-occurring ZHx2-null mutant. C3H mice carry a permissive allele of a second repressive gene, Afr2, which allows persistent AFP expression after liver regeneration [142]. Neither the ZHx2-null mutant nor the permissive allele of Afr2 are associated with developmental abnormalities or liver pathology.…”

Forkhead Box A2–Mediated Regulation of Female-Predominant Expression of the MouseCyp2b9Gene

“…4. The predicted sequence was found at Ϫ207/Ϫ203 for FoxA2 (HNF3␤), which was isolated as a transcription factor highly expressed in the liver (Spear et al, 2006). We then attempted to prove that the sequence between Ϫ207 and Ϫ203 was critical for femalepredominant expression in the liver.…”