#Gene decode upgrade

'To capture H3K79me2 “readers”, we must upgrade our 'bait' and 'hook',“ said Li. Second, the interaction between the 'readers' and H3K79me2 can be weak or even transient and thereby easily lost during the 'fishing' process. In other words, recognising H3K79me2 by its 'readers' may require a native nucleosome- or chromatin-context. First, 'reading' the marks may involve not only the mark itself but also the whole histone and even the histone-DNA complex called a nucleosome. 'It is a great challenge to identify H3K79me2 “readers”, even with our previously developed novel chemical approaches,' said Professor Li. In fact, over the years, many labs have tried various approaches to look for these 'readers'. On the other hand, H3K79me2 has been found at abnormally high levels and in the wrong places (e.g., cancer-promoting genes) in a variety of cancers such as childhood leukaemia.ĭespite its biological significance in gene regulation, the mechanism of how this mark is 'translated' is unclear, as the 'readers' of H3K79me2 have not been found since its discovery 20 years ago. Loss of H3K79me2 in mammalian embryos can lead to multiple developmental abnormalities, including impaired growth, cardiac dilation, and death. In human cells, this mark is found in actively expressed genes. In this study, the team focused on a methylation mark at histone H3 lysine 79 (H3K79me2).

'The key to success is not only the 'bait' but also a specially designed 'hook' that is equipped with a light-activated chemical group to capture the 'readers' upon exposure to UV light,' explained Professor Li. One such method uses a peptide containing a histone mark (i.e., a small fragment of histone protein) that acts as the 'bait' to 'fish' for 'readers' that recognise the mark. A long-standing interest of Professor Li’s lab is the development of novel chemical approaches to identify histone 'readers' that might be difficult to find using traditional biological methods. However, 'readers' of many histone marks are still unknown, which limits our ability to understand their roles in gene regulation. To answer this question, it is essential to find the 'readers', a class of proteins that recognise specific histone marks and 'translate' them by turning the expression of genes up or down accordingly. One of the challenges in chromatin biology is how particular histone marks are interpreted to achieve their biological function. Misregulation of this fundamental process underlies many severe human diseases such as cancers.ĭifferent types of histone marks act as cellular signals to control various chromatin-associated machineries that regulate gene expression, DNA replication, and damage repair. We now know that these histone modifications are tags or marks on chromatin that function as master switches for the regulation of genes - they determine which sets of genes in a cell should be 'ON' or 'OFF' at the right time and to the right extent. This fundamental process is regulated by diverse modifications of histone proteins, which were previously thought as mere spools for packaging DNA in the nucleus of our cells. Therefore, to make a specific cell type (e.g., a stem cell, a neuron), each cell needs to carefully 'choose' which genes to express.

The findings were recently published in Science.Įach type of cell in the human body (with some exceptions) contains exactly the same DNA sequence known as genes. A research team from the University of Hong Kong (HKU) led by Professor Xiang David LI from the Department of Chemistry in collaboration with Dr Yuanliang ZHAI from the HKU School of Biological Sciences and Dr Jason Wing Hon WONG and Dr Xiucong BAO from the HKU School of Biomedical Sciences recently made a key breakthrough in understanding how genetic information encoded in our DNA is 'read' and why errors in 'reading' such information can often lead to developmental defects or cancers.