**4. Concluding remarks**

In the past decades, particularly recent years, significant achievements have been made in epigenetic study particularly 5-mC and its derivatives such as 5-hmC, 5-fC, and 5-caC, in understanding the generation, dynamic alteration, machinery, distribution, and biological functions and connection between the modifications and the pathogenesis of diseases such as neurological disorders and cancers. However, a large number of unknown epigenetic events related to pathogenesis of many diseases particularly cancers remain to be elusive. Although the individual members of the methyltransferase complexes (writer) for cytosine modifications have been characterized, their coordination in conducting the methylation in response to tumorigenesis has not yet been comprehensively investigated. Similarly, the functional study on the TET proteins (the erasers for methylation) stays only at the conversion of 5-mC to 5-hmC, identification of the targeting miRNAs, and identification of serving as tumor suppressors or promoters by several known mechanisms. However, it is logical to speculate that as such huge protein molecules, TET proteins may have much more unidentified functions. Further study on the unknown functions will provide essential information for dissecting the cancer pathogenesis. First, only limited information is available for the physical interaction components of the TETs; identification of the TET interaction proteins may help us better understand how and where the TETs are recruited to function as demethylase to maintain the dynamic balance of 5-mC/5-hmC and the chromatin remodeling. Then, identification of other functions of TETs other than demethylase will be of importance. Given that the 5-hmC is not so much serving an intermediate of demethylation as the important dynamic 5-hmC landscape, it is essential to investigate how the epigenetic information stored in the landscape is transformed into the biological effect. To this end, for identification of the readers of the 5-hmC modification, the specific 5-hmC binding proteins might be the prerequisite. A better understanding the functions of methyltransferase complex for cytosine methylation, TETs for demethylation of 5-mC and interaction protein components as well as the other known functions, and the specific readers of the 5-hmC marker could identify some epigenetic components for therapeutic targets for treatments of cancers and other diseases such as neurological disorders.

It has been reported that Tet1 alternative splicing forms have distinct functions [74]. However, the information regarding the Tet1 alternative splicing is still limited. Further alternative splicing study may identify more unknown functions conferred by the different isoforms which may bear the potential for therapeutic targets.

Additionally, the chemical biology approach based on further identification of small molecule compounds that target the 5-mC/5-hmC machineries or the signaling pathways in which 5-mC/5-hmC involved could help explore therapeutic targets for some stubborn diseases such as cancers and neurological diseases.
