Striking differences between the mouse and the human alpha-fetoprotein enhancers

Area of Science:

• * Molecular biology
• * Genetics
• * Hepatology

Background:

• The alpha-fetoprotein (AFP) gene is highly expressed in fetal liver, repressed in adults, but reactivated in liver regeneration and tumors.
• Previous research identified three enhancers (E1, E2, E3) upstream of rodent AFP genes and one upstream of the human gene.

Purpose of the Study:

• To compare the regulatory sequences upstream of rodent and primate AFP genes.
• To identify conserved and divergent regulatory elements and transcription factor binding sites.

Main Methods:

• Comparative sequence analysis of rodent and primate AFP gene regulatory regions.
• Identification and characterization of enhancer elements and transcription factor binding motifs.

Main Results:

• The human enhancer corresponds to mouse E2; a functional primate counterpart to rodent E1 is absent due to a deletion.
• A novel human enhancer (E3 counterpart) was identified, showing differences in transcription factor binding sites compared to rodents.
• Specific binding sites for orphan nuclear receptors and FoxA proteins in rodent E3 are not conserved in humans; human E3 binds COUP-TF factors.

Conclusions:

• The absence of the E1 enhancer and differences in E3 transcription factor binding sites suggest distinct mechanisms regulate AFP transcription in primates versus rodents.
• Comparative genomics reveals species-specific regulation of AFP gene expression.