Fudan finds the "switch" of gene activity that inhibits cancer, and the new drug will be listed in 5 years.
Release date: 2016-04-13 "After five years of hard work, the switch of gene activity regulation has finally been found. There are new ideas for cancer treatments that are plaguing people's health such as lung cancer and breast cancer." Recently, Professor Lan Fei of the Institute of Biomedical Sciences (IBS) of Fudan University told excitedly澎湃News: “Optimistically, after another 5 years or so, new drugs developed according to this research will be available.†The most cutting-edge new discovery by Prof. Lanfei from the Institute of Biomedical Sciences (IBS) of Fudan University and Prof. Shi Yang, Professor Shi Yujiang, was recognized by the world's three most prestigious academic journals on April 7. One of the Cell magazines was published. The above studies found that in cancer cells, the loss of control of the enhancer in chromatin over-enhanced the activity of nearby oncogenes, leading to abnormal cells and even cancer. The study also found that the protein RACK7 and demethylase KDM5C present in this region can limit the activity of such enhancers, keep gene expression in the normal range, and thus inhibit cancer. Genetic mutation is not the only cause of changes in organism traits More than half a century ago, scientists discovered the basis of DNA (deoxyribonucleic acid) as the main genetic material in cells, opening the era of molecular biology. A fragment of genetic information carried on DNA, often referred to as a gene. During the long evolutionary process, DNA sequences undergo slow mutations to adapt to changes in the environment. For a long time, according to Darwin's theory, the academics believed that the changes in the traits of organisms were caused by genetic mutations and natural selection. Such changes were dramatic and irreversible. However, in reality, the rate at which organisms adapt to the external environment is much higher than the rate of gene mutation. This indicates that the rate of change of many biological phenomena is much higher than the frequency of DNA changes, and the DNA sequence itself cannot fully cope with external environmental changes. In fact, there is another substance on the chromatin that is the carrier of genetic material - histone. Histones wrap around DNA strands to support and protect DNA. While conserving the genome, they also regulate the expression of genes: by changing the activity of related factors to change the release of DNA signals, controlling the output of the genetic database, and then regulating the extrinsic traits of organisms. In the past, the academic community generally believed that the role of histones was to stabilize DNA and did not have much research value. Until the end of the 1990s, researchers found that chemical modifications on histones may have a switching function that controls the activity of genes, and the importance of histone modifications is thus determined. Find regulatory "switches" for gene activity Professor Lan Fei's research team and Professor Shi Yang-Shi Yujiang's research team's discovery is like finding a "switch" for gene activity on histones. Histone methylation is a universal and critical modification that functions as a "tag" to DNA to tell the genome how a particular DNA sequence encodes and what it does. The subject of this study, methylation at the 4th lysine (H3K4) of histone H3, was used to label the DNA activity of this segment. The lysine may be present in a variety of methylation states, and it is generally believed that its hypermethylated state (H3K4me3) occurs in the initiation region of the gene, while the hypomethylated state (H3K4me1) marks the enhancer region. Although the enhancer itself is not a gene, it is crucial for the regulation of nearby gene activity. The loss of control of the enhancer can directly lead to the loss of control of the activity of the nearby gene. The study by Fudan University unexpectedly found that H3K4me3 can also occur in the enhancer region, labeling the over-activated state of the enhancer, and enhancing the nearby oncogene activity and cell transfer ability, which is easy to cause cancer. The research team found a protein called RACK7, which attracted a histone demethylase called KDM5C, which transformed the original hypermethylation state into a hypomethylated state, keeping the surrounding gene expression in place. Normal range, thereby preventing cell cancer. Enhancer regulation mechanism can be applied to cancer treatment According to Lan Fei, this research was started as early as 2011, and the initial progress was not smooth. "This RACK7 protein is hidden in the winding path. We know that there is a magnificent spectacle behind it, but it can never be Have a glimpse of the door." Until the beginning of 2014, the co-first author of the thesis, Shen Hongjie, a postdoctoral fellow of the Institute of Biomedical Research, and the Ph.D. student, Xu Wenzhao, unexpectedly discovered that the “enhancer over-activated state†and its association with RACK7, which “touched the pulseâ€. Subsequent research is also a matter of course. In fact, since it is easier to change the enhancer activity than to change the gene sequence, it has great application prospects, and it has become a research hotspot in the field of epigenetics in recent years. It was only before this new discovery that the academic community did not realize that the methylation dynamics of H3K4 occurred on the enhancer, and thus the specific mechanism of this regulation was not found. It is worth mentioning that Fudan and Harvard double-employed professor Shi Yang is one of the founders and pioneers in the field of histone demethylation. As early as 2004-2007, he and the Dr. Shi Yujiang and Dr. Lan Fei, who were still working in their laboratories, discovered the first histone demethylase LSD1 and other multi-type demethylases in the world. , including the KDM5C involved in this study. The discovery of demethylase not only proves that histone methylation is reversible, but also lays a theoretical foundation for the methylation modification involved in the dynamic regulation of gene activity. Twelve years later, the discovery of Professor Lan Fei's research team and Professor Shi Yang-Shi Yujiang's research team has taken the research in this field a step further. Lan Fei said with a smile: "At that time, only the histone methylation was known as the 'tag' on the genome. The 'tag' can be affixed or torn off, but the specific functions of many 'tags' are not clear. Accumulation, already knowing what more and more 'tags' are doing, and knowing which factors are 'posting' and 'tearing' them under what circumstances." This discovery not only discovers the new law of epigenetic modification self-regulation of genomic information, but also puts forward the theory of “enhancer over-activation state†and more importantly its potential medical value: RACK7 and KDM5C exist in many cancer cases. The mutation phenomenon cannot limit the activity of the enhancer, so that the gene which should be kept low is abnormally activated. Nowadays, this mechanism has been revealed, which not only provides a new theoretical explanation for cancer occurrence, but also provides new drug targets and treatment ideas for personalized treatment of cancer. Source: 澎湃News
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