A analysis group from the College of Hong Kong (HKU) led by Professor Xiang David Li from the Division of Chemistry in collaboration with Dr Yuanliang Zhai from the HKU College of Organic Sciences and Dr Jason Wing Hon Wong and Dr Xiucong Bao from the HKU College of Biomedical Sciences just lately made a key breakthrough in understanding how genetic info encoded in our DNA is ‘learn’ and why errors in ‘studying’ such info can typically result in developmental defects or cancers. The findings had been just lately revealed in Science.
Every kind of cell within the human physique (with some exceptions) comprises precisely the identical DNA sequence generally known as genes. Subsequently, to make a selected cell kind (e.g., a stem cell, a neuron), every cell must fastidiously ‘select’ which genes to precise. This elementary course of is regulated by numerous modifications of histone proteins, which had been beforehand thought as mere spools for packaging DNA within the nucleus of our cells. We now know that these histone modifications are tags or marks on chromatin that operate as grasp switches for the regulation of genes — they decide which units of genes in a cell needs to be ‘ON’ or ‘OFF’ on the proper time and to the best extent. Misregulation of this elementary course of underlies many extreme human illnesses akin to cancers.
Several types of histone marks act as mobile alerts to regulate varied chromatin-associated machineries that regulate gene expression, DNA replication, and injury restore. One of many challenges in chromatin biology is how specific histone marks are interpreted to realize their organic operate. To reply this query, it’s important to search out the ‘readers’, a category of proteins that acknowledge particular histone marks and ‘translate’ them by turning the expression of genes up or down accordingly.
Nonetheless, ‘readers’ of many histone marks are nonetheless unknown, which limits our skill to know their roles in gene regulation. A protracted-standing curiosity of Professor Li’s lab is the event of novel chemical approaches to determine histone ‘readers’ that is likely to be troublesome to search out utilizing conventional organic strategies. One such methodology makes use of a peptide containing a histone mark (i.e., a small fragment of histone protein) that acts because the ‘bait’ to ‘fish’ for ‘readers’ that acknowledge the mark.
The important thing to success is just not solely the ‘bait’ but additionally a specifically designed ‘hook’ that’s outfitted with a light-activated chemical group to seize the ‘readers’ upon publicity to UV mild.”
Professor Xiang David Li, Division of Chemistry, HKU
On this examine, the group targeted on a methylation mark at histone H3 lysine 79 (H3K79me2). In human cells, this mark is present in actively expressed genes. Lack of H3K79me2 in mammalian embryos can result in a number of developmental abnormalities, together with impaired progress, cardiac dilation, and dying. Then again, H3K79me2 has been discovered at abnormally excessive ranges and within the mistaken locations (e.g., cancer-promoting genes) in a wide range of cancers akin to childhood leukemia.
Regardless of its organic significance in gene regulation, the mechanism of how this mark is ‘translated’ is unclear, because the ‘readers’ of H3K79me2 haven’t been discovered since its discovery 20 years in the past. In actual fact, over time, many labs have tried varied approaches to search for these ‘readers’. “It’s a nice problem to determine H3K79me2 “readers”, even with our beforehand developed novel chemical approaches,” stated Professor Li. There are two main hurdles to beat. First, ‘studying’ the marks might contain not solely the mark itself but additionally the entire histone and even the histone-DNA advanced known as a nucleosome. In different phrases, recognizing H3K79me2 by its ‘readers’ might require a local nucleosome- or chromatin-context. Second, the interplay between the ‘readers’ and H3K79me2 could be weak and even transient and thereby simply misplaced in the course of the ‘fishing’ course of.
“To seize H3K79me2 “readers”, we should improve our ‘bait’ and ‘hook’,” stated Li. However it was not trivial. Li’s lab spent greater than 5 years creating their new device. As a substitute of utilizing a small fragment of the histone protein, they chemically synthesized an intact nucleosome with an upgraded tri-functional ‘hook’ and H3K79me2 because the ‘bait’ (Determine 2). Utilizing this new know-how, the group efficiently recognized a protein known as menin because the ‘reader’ of H3K79me2.
To know how menin ‘reads’ the H3K79me2 mark, the group adopted a cutting-edge know-how known as cryo-electron microscopy to visualise the molecular particulars of this interplay. “Unravelling the small print of how menin binds H3K79 methylation is essential to designing new medicine to deal with cancers related to misregulated H3K79me2,” stated Professor Li.
The pioneering work by Li and associates have superior our understanding of the elemental organic processes of gene regulation. These findings additionally open new alternatives for creating novel therapeutic brokers to deal with human illnesses brought on by irregular ranges of H3K79 methylation.
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