It has been known for decades that mammalian DNA cytosine bases have two modifications: 5-methylcytosine and 5-hydroxymethylcytosine.Over the years, 5 mC has been widely studied as an important epigenetic modification, participating in gene expression regulation, X-chromosome inactivationGenomic imprintingThe long-term silence of transposons and the occurrence of cancer are called the fifth base of the genome;However, the existence of 5-hydroxymethylcytosine has not been confirmed due to technical limitations. In recent years, the application of high-precision mass spectrometry has improved the situation;At the same time, it was also found that the formation of 5-hydroxymethylcytosine was related to malignant hematological tumors, which promoted the research in this field. A series of significant advances in its biosynthesis, function, tumor clinical application research and detection technology were soon made, and a brief review was made.
1 Biosynthesis
In recent years, a series of studies have shown that TET (10-11 translocation Ten Eleven Transportation) family oxygenase catalyzes the conversion of 5mC to 5hmC, and its biological process is shown in Figure 1.Cytosine, as DNA, is composed of cytosine 5-methylcytosine5-hydroxymethylcytosine(Cytosine C) (5-methylcytosine 5mC)Methyl donor, add methyl on the 5 position of cytosine base to form 5-methylcytosine.Then, under the action of TET family proteins, hydroxyl is transferred to 5-methylcytosine by molecular oxygen to form 5-hydroxymethylcytosine [1,4].TET family proteins are the key molecules for the synthesis of 5-hydroxymethylcytosine from 5-methylcytosine.In acute myeloid leukemia, TET1 gene is the fusion partner of MLL gene translocation, which is located on chromosome 10q24 and 11q23, respectively.TET protein is a 2-ketoglutarate (2-oxoglutarate 2OG) and Fe (II) dependent enzyme. Studies have proved that it can catalyze the conversion of 5-methylcytosine to 5-hydroxymethylcytosine in cultured cells and in vitro.
5-hydroxymethylcytosine exists in the genome of mouse embryonic stem cells. After depletion of TET1 mediated by RNA interference, the level of 5-hydroxymethylcytosine decreases;It is believed that the modification of 5-methylcytosine to 5-hydroxymethylcytosine through TET protein should have potential epigenetic regulation [1,4].
2 Distribution and function in genome and different tissues
2.1 Distribution in mammalian genome
Cytosine methylation markers in mammalian genomes are not randomly distributed and may be related to their functions.For example, 5-methylcytosine is involved in the regulation of gene expression, which is mostly located in CpG dinucleotides in gene regulatory regions such as promoters;While most of 5-methylcytosine is located in transposons, the latter can damage the function and stability of the genome due to the repeated sequence in the group. When various types of transposons are intensively methylated, their activity is silenced in all types of cells [1].Because 5mC and 5hmC are highly similar, the currently widely used bisulfite based technology cannot distinguish between the two modifications, so there is an urgent need to develop a specific genomic technology to detect 5hmC. At present, some progress has been made and new information on the distribution of hmC genomes is being accumulated [5].In 1972, the presence of 5-hydroxymethylcytosine was first reported in the brains of adult rats and frogs, accounting for~15% of the total cytosine in the extracted DNA. Since then, it has not been repeated, and has not received due attention for more than 30 years.In 2009, the application of new technology began to accumulate valuable information about the distribution of 5-hydroxymethylcytosine in various tissues [1].If some authors use HPLC-MS and immunohistochemistry to show that hmC exists in all tissues and cell types, and has the highest concentration in nerve cells of the central nervous system [5].
Recently, the newly developed 5-hmC immunological technology was used to determine the abundance of 5-hmC in human tissues and compare the 5-hmC status between normal and cancerous colorectal cancer tissues.A significant difference in 5-hmC content was observed between different tissues.The proportion of 5-hmC detected in total nucleotides is high in brain, liver, kidney and colon cancer tissues (0.40-0.65%), relatively low in lung (0.18%) and very low in heart, breast and placenta (0.05-0.06%).Compared with the normal colorectal tissue (0.46-0.57%), the 5-hmC abundance of colorectal cancer tissue was significantly reduced (0.02-0.06%).The above results show for the first time that the distribution of 5-hmC in human tissues is tissue dependent, and its abundance in disease state is as followsColorectal cancerCan be changed [6].Another group of authors studied the distribution of 5 hmC in a group of rats and human tissues using immunohistochemical detection methods, and found that most embryonic stem cells and adult tissues were rich in 5 hmC;In multi-level and orderly tissues, the level of 5 hmC is closely related to the differentiation status of cells.The highest level of 5 hmC was observed in the terminally differentiated cells, while a very low level of 5 hmC was found in the less differentiated stem cells/progenitor cells;Moreover, compared with normal tissues, the level of 5 hmC in various cancer tissues decreased significantly.The results showed that 5 hmC played an important role in tissue differentiation and lost a lot of 5 hmC in cancer [7].
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Xue Kaixian, Department of Genetics, Jiangsu Cancer Institute
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