Epigenetic modulation

DNA methylation and demethylation

Kyun-Hwan Kim

Department of Pharmacology, Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Korea

Cytosine methylation is a DNA modification generally associated with transcriptional silencing of genes. DNA methylation in mammals is a key epigenetic modification essential to normal regulation and development. The pattern of DNA methylation at bases in the genome is tightly linked to gene expression, and DNA methylation abnormalities are often observed in diseases. DNA methylation patterns are established during early , and subsequently maintained dur- ing cell divisions. Yet, discrete site-specific de novo DNA methylation or DNA demethylation events play a funda- mental role in a number of physiological and pathological contexts, leading to critical changes in the transcrip- tional status of genes such as differentiation, tumor suppressor or imprinted genes. The ubiquitously expressed DNA methyltransferase DNMT1 is predominantly responsible for copying and main- taining DNA methylation pattern after DNA replication, while the de novo DNA methyltransferases DNMT3A and DNMT3B are involved in the establishment of new DNA methylation patterns. Two main demethylation pathways have been described over the years. Methyl-CpG can be passively removed by blocking methylation of newly synthesized DNA during DNA replication. The methyl-group can also be enzymati- cally oxidized by the TET (ten-eleven translocation methylcytosine dioxygenase) family enzymes to give rise to 5-hydroxy-methyl-CpG (5hmC; and other oxidized bases) and subsequently removed by a base-excision repair (BER) pathway to re-introduce an unmodified cytosine. DNA demethylation is essential and it plays a predominant role in resetting gene expression in early , in developing germ cells, and in adult tissues. Recently, numerous studies demonstrated that epigenetic changes in liver cells are associated with liver diseases. The typical epigenetic lesions in liver cancer include genome-scale changes in the DNA methylation landscape, lo- ci-specific DNA hypermethylation, and abnormal expression of ncRNAs. Cancer-related changes in DNA methyl- ation are attractive as biomarkers since they can be readily detected and quantified from fixed tissues. As a con- sequence, there are many published studies reporting DNA methylation patterns specific to liver cancers of differ- ent etiologies. Here, I will present the basic knowledge of DNA methylation and demethylation, detection of methylation status, and relationship between methylation and liver diseases.

Keywords: Methylation; Demethylation; Epigenetic regulation; DNMT; TET

50 대한간학회 김균환 | DNA methylation and demethylation

www.kasl.org 51 제22차 대한간학회 추계학술대회

52 대한간학회 김균환 | DNA methylation and demethylation

www.kasl.org 53 제22차 대한간학회 추계학술대회

54 대한간학회 김균환 | DNA methylation and demethylation

www.kasl.org 55