Bioactive Small Molecules for Epigenetic Research
The term "epigenetics" was first proposed by Conrad H. Waddington in 1942.1) Epigenetics is the study of acquired chemical modifications of DNA and nuclear histone proteins that do not alter the DNA sequence but regulate gene expression and other processes that occur during development, cell differentiation, and carcinogenesis.2) Among others, DNA methylation and histone modification are two well-researched physiological mechanisms of epigenetic change.3,4)
Mechanism of DNA methylation
Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosine. In mammals, methylating the cytosine within a gene can change its expression, a mechanism that is part of a larger field of science studying gene regulation called epigenetics. The enzymes that add methyl groups are called DNA methyltransferases and those that remove methyl groups are called DNA demethylases. Three types of each group have been identified in mammals.
Mechanism of Histone deacetylase (HDAC)
Genomic DNA is packaged in the nucleus as nucleosomes, each individual nucleosome consisting of a segment of DNA is wrapped around proteins called histones. Histone deacetylase (HDAC) is an important enzyme regulating gene expression by changing nucleosome structure. Numerous histone acetylases and deacetylases have been identified to date. HDAC is also thought to have a regulatory role in the cell cycle and cell differentiation, and the failure of this regulation has been associated with carcinogenesis. In a mouse model, SAHA (TCI Product No. H1388) inhibits HDAC activity by inducing the differentiation and/or apoptosis of transformed cells in vitro, thereby inhibiting tumor growth.
Inhibitor of Lysine-specific Demethylase (LSD)
LSD (lysine specific demethylase) is an enzyme that demethylates methylated lysine in histone proteins using FAD (flavin adenine dinucleotide) as coenzyme. It is known that these two isoforms (LSD1 and LSD2) epigenetically regulate gene expression. Aberrant expression of LSD1 is implicated in the maintenance of cancer stem cells and is expected to be a therapeutic target for cancer.5,6) LSD2 interacts with nucleosomes differently from LSD1 and plays a different biological role.7)
TCI offers LSD Inhibitor S1024 (TCI Product No. B6490) and LSD Inhibitor S1025 (TCI Product No. B6491).8)
- 1) The Epigenotype
- 2) Epigenetic mechanisms of gene regulation, ed. by R. A Martienssen, A. D Riggs, V. E. A. Russo, Cold Spring Harbor Laboratory, New York, 1996.
- 3) Epigenetic Gene Regulation in the Bacterial World
- 4) Developmental roles of the histone lysine demethylases
- 5) LSD1/KDM1A, a gate-keeper of cancer stemness and a promising therapeutic target
- 6) Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation
- 7) Structural insight into inhibitors of flavin adenine dinucleotide-dependent lysine demethylases
- 8) Structure–Activity Relationship and In Silico Evaluation of cis- and trans-PCPA-Derived Inhibitors of LSD1 and LSD2