The 16th symposium

Speech

Special　Lecture1

“Molecular basis of pathophysiology regulated by epigenomic memory”
Mitsuyoshi Nakao
Professor, Institute of Molecular Embryology and Genetics, Kumamoto University

Species conservation and evolution depend on ‘genome editing’, while development and environmental adaptation are controlled by ‘epigenome editing’. Particularly, epigenetic memory and the resulting gene regulation occur against repeated environmental factors during development. After that, if the same environmental factor acts, the body can be adapted quickly, but if the environmental factor changes, it is likely to become incompatible. This represents ‘DOHaD (Developmental Origins of Health and Disease) theory’.
We reported that the flavin-dependent lysine demethylase LSD1 epigenetically regulates energy metabolism under environmental conditions. LSD1 inhibition in adipocytes and adipose tissues promoted oxidative phosphorylation and energy expenditure, resulting in a reduction of obesity and insulin resistance. In addition, LSD1, which is highly expressed in cancer cells, suppressed oxidative phosphorylation and stabilized HIF-1 to activate a metabolic pathway dominated by glycolysis (Warburg effect). We also found that LSD1 controls the balance of muscle fiber types (fast/slow muscles) and metabolic types (glycolysis/oxidative phosphorylation) in skeletal muscles. LSD1 inhibition enhanced slow muscle differentiation and oxidative phosphorylation. Thus, LSD1 activities regulate metabolic phenotypes.
Furthermore, using the siRNA library, we identified that specific epigenetic factors (such as histone methylases SETD8 and NSD2) protect cellular senescence. We will discuss the significance of epigenetic memory and phenotypic variation from a view of epigenome and metabolic remodeling, and the new integrated platforms that automatically analyze various types of multi-omics data such as epigenome, transcriptome and proteome.

Special　Lecture2

“Regulation of histone modifications by a novel non-coding RNA with repetitive sequences that suppresses the hepatitis B virus”
Ai Kotani
Department of Regulation of Infectious Cancer, Research Institute for Microbial Diseases, Osaka University

The genome of the hepatitis B virus (HBV) consists of circular DNA. When HBV infects human hepatocytes, it deposits covalently closed circular DNA (cccDNA) in the nucleus of those cells that is retained for life. Therefore, existing drugs that inhibit virus production require lifelong use, which is a serious problem with the treatment of HBV. We have identified a novel cccDNA-binding non-coding RNA (ncRNA) with several unique 7-nucleotide repeats that are induced by Toll-like receptors (TLRs). This ncRNA significantly reduces cccDNA by downregulating pregenomic RNA (pgRNA) in a repeat-dependent manner. The ncRNA forms a protein-RNA complex with HDAC2 via EEF1A1 and recruits HDAC2 to loci containing HBV target loci and host super-enhancers, suggesting an epigenetic mechanism of action that results in significant H3K27 deacetylation and BRD4 removal. These results indicate that ncRNAs help to determine the target specificity of H3K27 deacetylation to defend the host against pathogens and that those ncRNAs may be therapeutic targets.