Genomics Research Center, Academia Sinica

Knowing all DNA sequences is enough to solve the mystery of the great diversity and complexity of life? Scientists have now put the idea aside since very little is different in DNA sequence between human and chimpanzees. Instead, the events that control gene expression from DNA to RNA without altering the DNA sequence, the phenomenon so called “epigenetic regulation”, has jumped on the center of the stage!

A group of the researchers at Genomics Research Center (GRC) of Academia Sinica in Taiwan recently identified a new mechanism for histone modifier RBP2, a key player in epigenetic regulation, to target specific DNA. This is an exciting finding and has been reported with highlight as Advance Online Publication by Nature Structural and Molecular Biology (NSMB) on 2/12 prior to its print release scheduled later.

DNA that holds the myth of biological functions is wrapped by positively charged histone proteins inside the nucleus. Histones are key elements that control the gene behaviors. Of the 23 pairs of DNA strings within the nucleus of each human cell, each DNA string has beads-like forms along the string representing meaningful genes. It is estimated that approximately 25,000 genes are buried in these beads in human cells. Scientists have observed that certain beads may open up to affect specific cell functions. Should beads open when they are not supposed to, an irregular cell disaster will occur. That may ultimately lead to cancer formation.

The reason the beads crack open is due to modification of the chemical structure of the histone wrapping a gene segment. There exist many enzymes floating within the nucleus and waiting for chances to bind with the DNA or to modify histones. Whenever a histone is modified and let go of its neighboring DNA, there lies the chance of a gene behavior change.

Dr. Tsai (left) and Dr. Juan (right)

So, how can histones be modified? Back in 1964, the modification of histones with methyl groups (A –CH3 structure) was already identified. Yet, only recently did scientists actually catch the enzymes for methyl addition and removal. By the end of 2007, Dr. Ming-Daw Tsai’s group was one of the first groups in the world that proved the tri-methyl groups can be deleted from histones. The significance of this finding was that it confirmed the role of histone decorated with three methyl groups as optional modifiers to DNA, not part of the genetic inheritance codes.

Juan’s studies in cells further indicated that ARID is required for RBP2 demethylase activity and that DNA recognition is essential for RBP2 to regulate transcription.

“This work is very interesting considering that few histone modifiers recognize specific DNA sequences.” said Tsai, “We solved the first structure of the DNA binding domain of a histone demethylase and dig out the binding sequence on DNA.”

This study was led by Dr. Ming-Daw Tsai and Dr. Li-Jung Juan. Juan is an assistant research fellow who has been studying functions of histone modifiers for years. Dr. Ming-Daw Tsai, a distinguished research fellow of GRC also heads the Functional Genomics Division and the Institute of Biological Chemistry. Tsai is a structural biologist whose main interest has been proteins in cell cycle progression and his involvement with histones was only recently. Other members of this research include Dr. Ying-Ta Wu, Miss Yu-Ching Teng, a Ph. D. student from the Department of Biochemistry, National Yang Ming University, and Shengjiang Tu, a Ph. D. student from the Department of Chemistry, Ohio State University.

“It has been a wonderful experience of collaboration.” said Juan, “As a molecular biologist, I did imagine working with NMR and the structure stuffs when I joined GRC in 2006, but I never thought it would happen so quickly and have such successful result!”

More excitingly, recent data indicate cancer cells tend to produce more RBP2. “It will be a good drug candidate if an anti-cancer compound to control histone methylation is going to be developed.” said Juan.