Chemical Control System of Epigenetics.

Epigenetics represents the inheritable changes to the chemical control system governing the gene expression with no ensuing changes to the underlying DNA sequence. Environment-mediated modification of the natural epigenetic interactions can perturb the cellular homeostasis and drive cells to a diseased state by switching therapeutically essential genes ON and OFF. Contemporary bioinformatics tools have revealed the structural chemical modifications of the epigenetic enzymes associated with several complex diseases, including cancers, immune disorders, and neurodegenerative disorders at the fundamental level.

A Multi-target Small Molecule for Targeted Transcriptional Activation of Therapeutically Significant Nervous System Genes.

An integrated multi-target small molecule capable of altering dynamic epigenetic and transcription programs associated with the brain and nervous system has versatile applications in the regulation of therapeutic and cell-fate genes. Recently, we have been constructing targeted epigenetic ON switches by integrating sequence-specific DNA binding pyrrole-imidazole polyamides with a potent histone deacetylase inhibitor SAHA. Here, we identified a DNA-based epigenetic ON switch termed SAHA-L as the first-ever multi-target small molecule capable of inducing transcription programs associated with the human neural system and brain synapses networks in BJ human foreskin fibroblasts and 201B7-iPS cells.

Ligand-Mediated G-Quadruplex Induction in a Double-Stranded DNA Context by Cyclic Imidazole/Lysine Polyamide.

G-quadruplex (G4) DNA is often observed as a DNA secondary structure in guanine-rich sequences, and is thought to be relevant to pharmacological and biological events. Therefore, G4 ligands have attracted great attention as potential anticancer therapies or in molecular probe applications. Here, we designed cyclic imidazole/lysine polyamide (cIKP) as a new class of G4 ligand.

Phylogeny and historical demography of endemic fishes in Lake Biwa: the ancient lake as a promoter of evolution and diversification of freshwater fishes in western Japan.

To elucidate the origins of the endemic fish of Lake Biwa, an ancient lake in Japan, and the role of the lake in the diversification of freshwater fish in western Japan, we established a molecular phylogenetic framework with an absolute time scale and inferred the historical demography of a large set of fish species in and around the lake. We used mtDNA sequences obtained from a total of 190 specimens, including 11 endemic species of Lake Biwa and their related species, for phylogenetic analyses with divergence time estimations and from a total of 2319 specimens of 42 species (including 14 endemics) occurring in the lake for population genetic analyses. Phylogenetic analysis suggested that some of the endemic species diverged from their closest relatives earlier (1.

A Synthetic DNA-Binding Domain Guides Distinct Chromatin-Modifying Small Molecules to Activate an Identical Gene Network.

Synthetic dual-function ligands targeting specific DNA sequences and histone-modifying enzymes were applied to achieve regulatory control over multi-gene networks in living cells. Unlike the broad array of targeting small molecules for histone deacetylases (HDACs), few modulators are known for histone acetyltransferases (HATs), which play a central role in transcriptional control. As a novel chemical approach to induce selective HAT-regulated genes, we conjugated a DNA-binding domain (DBD) "I" to N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-benzamide (CTB), an artificial HAT activator.

Simulation of granular jets: is granular flow really a perfect fluid?

We perform three-dimensional simulations of the impact of a granular jet for both frictional and frictionless grains. Small shear stress observed in the experiment [X. Cheng et al.

Purification and characterization of Caenorhabditis elegans NTH, a homolog of human endonuclease III: essential role of N-terminal region.

Oxidatively damaged bases in DNA cause many types of deleterious effects. The main enzyme that removes such lesions is DNA glycosylase, and accordingly, DNA glycosylase plays an important role in genome stability. Recently, a relationship between DNA glycosylases and aging has been suggested, but it remains controversial.

Alkylation of template strand of coding region causes effective gene silencing.

We recently developed a new type of pyrrole (Py)-imidazole (Im) polyamide-tetrahydrocyclopropabenzindolone (CBI) conjugate with an indole linker as a stable sequence-specific alkylating agent. In this study, we investigated the gene silencing activities of polyamides A, B and C, which selectively alkylate specific sequences in the promoter region, non-coding strand and coding strand, respectively, of the green fluorescent protein (GFP) gene. GFP vectors were transfected into human colon carcinoma cells (HCT116), and the cells were treated with 100 nM of the polyamides for 24 h.

Suppression of a mitotic mutant by tRNA-Ala anticodon mutations that produce a dominant defect in late mitosis.

Cold-sensitive dominant mutants scn1 and scn2 of Schizosaccharomyces pombe were isolated by their ability to suppress temperature-sensitive cut9-665 defective in an essential subunit (human Apc6/budding yeast Cdc16 ortholog) of anaphase promoting complex/cyclosome (APC/C). APC/C mutants were defective in metaphase/anaphase transition, whereas single scn mutants showed the delay in anaphase spindle elongation at 20 degrees C. The scn mutants lost viability because of chromosome missegregation, and were sensitive to a tubulin poison.