Huntington's disease is an autosomal dominant neurodegenerative disease. Its main pathological feature is the progressive death of neurons in the striatum of the brain. The mechanism by which the Huntington gene mutation causes selective death of striatum neurons is unclear, and there is currently no treatment. DNA cytosine methylation modification is an important way of apparent modification, and plays a key role in the process of chromosome remodeling, gene silencing, development and differentiation. Recent studies have confirmed that cytosine methylation can be further oxidized to hydroxymethylation modification. There is evidence that cytosine hydroxymethylation modification (5hmC) is involved in embryonic development, embryonic stem cell proliferation and differentiation, and neural cell differentiation There is an important role in maturity. The relationship between 5hmC modification of DNA and neurodegenerative diseases has not been reported.
The Molecular Neurobiology Research Group led by the researcher Tang Tieshan of the Institute of Zoology took yeast artificial chromosome transgenic chorea (YAC128-HD) mice as the research model, and systematically analyzed the 5hmC of brain tissues and different regions of brain tissues in different month-old disease models. Retouching level. The study found that the mouse's 5hmC level increased rapidly with the age of the month after birth, and reached the highest value at the age of three months; then the 5hmC level gradually decreased with the increase of the age. Compared with normal mice, the levels of cytosine hydroxymethylation in the striatum, cortex, and hippocampus of the diseased mice were significantly reduced, while the hydroxymethylation levels in the cerebellum and surrounding tissues were unchanged. These results suggest that there is a defect in the DNA construction of chorea in the construction of 5hmC. Genome-wide 5hmC analysis identified a series of differential 5hmC enrichment regions and differentially expressed genes related to chorea. Further pathway analysis revealed neural stem cell proliferation and development-related pathways (such as Wnt / b-catenin / Sox pathway, axonal guidance signaling pathway) and neuronal function and survival-related pathways (glutamate receptor / calcium / CREB, GABA receptor signaling, dopamine- DARPP32 feedback pathway etc) is closely related to the occurrence of diseases. These results reveal for the first time that the loss of 5hmC may be a new apparent characteristic marker of chorea, and it also opens up a new direction for the treatment of this disease.
The result was published online in the journal Human Molecular Genetics (First published online: May 12, 2013, doi: 10.1093 / hmg / ddt214). Wang Fengli, a PhD student in the research group, and other classmates are the co-first authors of the paper; Researcher Tang Tieshan, Researcher Han Chunsheng, and Researcher Caicai Guo of the Beijing Genomics Institute are co-corresponding authors. Researcher Sec. And Researcher Luo Huairong of Kunming Institute of Botany. The research was supported by the Ministry of Science and Technology, the National Natural Science Foundation of China and the Chinese Academy of Sciences.
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