SLUG is one of the most important candidate transcription factors upstream of JAGGED1, according to a preprint published in Research Square.

Identifying upstream regulatory transcription factors of JAGGED1 is important because it can shed light on the molecular mechanism behind JAGGED1 expression, the lack of which is associated with Alagille syndrome.

More than 90% of Alagille syndrome cases are caused by a mutation in the JAGGED1 gene. The JAGGED1 protein that this gene encodes normally plays a role in the epithelial differentiation of the bile ducts in the developing liver.


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In the absence of functional JAGGED1, normal liver physiology is disrupted. This leads to symptoms such as jaundice, pruritus, xanthomas, hepatomegaly, and splenomegaly.

Read more about Alagille syndrome symptoms 

Here, a team of researchers led by Satoru Takahashi, MD, PhD, Professor of Anatomy and Embryology at the University of Tsukuba in Japan used an integrated bioinformatics method to identify regulatory transcription factors upstream of JAGGED1. Using the DoRothEA database, they predicted 3 transcription factors to be upstream of JAGGED1. These were SLUG, SOX2, and EGR1.

According to previous single-cell RNA-seq analysis in 2 human fetal liver cells, SLUG and EGR1 were enriched in portal mesenchymal cells expressing the ACTA2 gene, which encodes smooth muscle alpha (α)-2 actin. Interestingly, portal mesenchymal cells expressing JAGGED1 were more likely to express SLUG than EGR1.

“These results would add mechanistic insights into developmental biology on how portal mesenchymal cells supports biliary development in the liver,” they concluded. This supports the hypothesis that SLUG induces JAGGED1 expression.

However, these results do not suggest that SLUG is the only regulatory candidate for JAGGED1 expression. More research is needed to elucidate the biochemical properties of portal mesenchymal cells to determine the relationships between transcription factors and the genes that they regulate.

Reference

Nishino T, Yoshihara M, Nakayama T, et al. Identifying potential regulators of JAGGED1 expression in portal mesenchymal cells. Res Sq. Published online February 17, 2022. doi:10.21203/rs.3.rs-1210544/v1