Senior Research Fellow
California Institute of Technology

A fundamental question in biology today concerns how complex tissue-specific and inducible gene expression is regulated.In eukaryotes, it is often difficult to ascribe specific roles to individual regulatory molecule or signal transduction pathways when several cues impinge simultaneously on a given gene.The net gene expression, therefore, must relate to the relative combinations of various transcription factors and accessory proteins, positive and negative, tissue-specific and ubiquitous that binds to the target DNA at any time.In the past decade the genomes of many organisms have been completely sequenced.Two striking observations are that those genomes contain significantly fewer genes than originally predicted and the majority of the DNA sequence contains regions of presently unknown function.It is therefore implicated that the majority increasing biological complexity of higher eukaryotes is critically dependent on the tightly directed expression of gene networks during their development (Levine and Tjian, 2003).

Clearly the function of transcription factors is dependent upon the specific DNA recognition elements.Changes in these elements may disturb the normal processes of gene regulation.Interestingly alterations to cis elements appears to be a relatively rare cause of disease.This is probably due to the co-operative multicomponent nature of transcription factor function and the importance of additional protein/protein interactions.The miss expression of transcription factors are the cause of many cancers.For example, c-myc overexpression is the cause of cancer.c-myc was shown to be over-expressed in this human B cell malignancy.The c-myc represents the example of proto-oncogenes.In contrast the p53 gene is the most mutated gene observed in human tumours.90% of missense mutations are in the DNA binding domain.The p53 is one of the examples of tumor suppressor genes.

I have long-term interests on endoderm/liver specific genes regulation since I was a graduate student.It is getting clearer that if we want to understand the cause of liver cancer, we have to understand the liver development.To understand the liver development, we need to dissect the gene regulatory network underlines the development of liver carcinogenesis.I therefore propose to study the GRN of liver development in order the understand the molecular mechanism of liver specific genes’ expression, eventually to derived some medical implications.

A comprehensive Gene Regulatory Network (GRN) for the endomesoderm specification has been proposed from our lab (Davidson et al, 2002).GRN talks about how an embryo forms endoderm and mesoderm by the integration of many signaling cascades (b-catenin/Wnt signaling, Notch signaling, micromere signaling et al.) and enormous transcription factors (Otx, Krox, GATA, homeobox Transcription factors et al.).The genomic regulatory code consists of the sequence specific templates for networks of cis-regulatory elements and trans-transcription regulatory factors.As numerous genomes have been completed, a striking truth has been revealed that a lot of important transcription factors are evolutionary conserved, and the function of most of the DNA region are unknown, those intragenic region were defined as “junk DNA”.Actually, they are the most important region for regulating the expression of genes at the right time and right places.Understanding the function of genes and the interrelationship of genes in regulating endomesoderm formation in sea urchin will benefit us to understand the basic of how the human genome works.GRN is composite with lots of signaling pathway integrated with lots of transcription regulators.Cell signaling cascades are part of normal cellular function and serve to regulate gene expression.Both cell signaling and gene regulations are controlled at a molecular level through formation of protein-protein interaction and protein-DNA interaction.After we understand all the molecular basis of interaction, we can design molecular medicine against the molecular interaction between protein-DNA and protein-protein interaction.The endomesoderm gene network is not only a blueprint of how genes work together to make the endoderm and mesoderm in sea urchin embryo, it also provides an tool to let us understand how those evolutionarily conserved transcription factors work together.

Since liver cell derived from endoderm lineage cell, it is possible that some the network we discovered in the Gene Regulatory Network for endomesoderm gene expression in sea urchin are similar in liver specification in higher organisms like vertebrate and human. The development of liver-specific function is a complicated process; it involved many signaling pathways as well as multiple transcription factors.We have to understand the Gene Regulatory Network of many genes involved in this complicated process in order to have the complete view of the molecular mechanisms.With the launch of the zebrafish genome project, it has been increasingly recognized that the zebrafish is an important animal model in biomedical research. I plan to use zebrafish for model system to investigate molecular mechanisms of liver development and liver cancers with respect to human medicine. It covers multi-disciplines: genomics and expression, toxicology and carcinogenesis, transgenesis with candidate proto-oncogenes, liver development and bioinformatics. I would like to continually my effort in this specific project by bring in state-of-the-art molecular and genetic of Gene Regulatory Network technologies to identify genes and molecular mechanisms involved in liver development. Furthermore, I would like to apply my research into medical application, for example, early cancer detection and therapy.

Yuh, C. H.Dorman E. R. and Davidson, E. H.
Brn1/2/4, the predicted midgut regulator of the Endo16 gene of the sea urchin embryo. Dev Biol. 2005 May 15;281(2):286-98.