Epigenomics alive and well in Japan

Written by Professor Ricky Johnstone, Peter MacCallum Cancer Centre, Australia

On October 17 2013, the 10th Nikko International Symposium was held at Jichi Medical University, Japan.  The theme for this year’s symposium was Translational Epigenomics, with invited speakers from throughout Japan, selected speakers from Jichi Medical University and two invited international speakers, myself and Dr Omar Abdel-Wahab from Memorial Sloan-Kettering Cancer Centre, USA.  Professor Keiya Ozawa, Director for the Center for Molecular Medicine, JichiS Medical University, was the convenor of the symposium and a gracious and energetic host.

 

A diverse array of oral presentations covering fundamental, translational and clinical epigenetics/epigenomics was provided to an enthusiastic audience.  Professor Yusuke Furukawa, Jichi Medical University, Japan, provided a contemporary update on the epigenetic reader, writer and eraser proteins that regulate the epigenome and the complex interplay between covalent modifications to histones and dynamic DNA methylation that regulates chromatin structure and gene transcription.  This provided the perfect background for an intriguing talk given by Dr Taeko Wada, Jichi Medical University, Japan, who demonstrated the functional difference between long and short splice isoforms of LSD1.  Dr Wada showed that the short LSD1 isoform produced following alternate splicing of exons 2 and 8 has higher affinity for the CoREST transcriptional cofactor, has enhanced demethylase activity and increases the self-renewal capacity of mouse LSK cells.  Knockdown of this LSD1 isoform inhibited the growth of leukemic cells providing evidence for an oncogenic role for this form of LSD1.  Dr Toshikazu Ushijima provided a provocative talk regarding the link between chronic inflammation caused by Helicobacter pylori (HP) infection and aberrant DNA methylation that results in a field effect termed “cancerization” by the author resulting in gastric cancer. Ushijima and colleagues have identified a gene set whose methylation levels distinguish gastric cancer patients from healthy individuals, even among individuals with past HP infection and pre-clinical studies demonstrated that 5-aza-dC prevented HP-induced gastric cancer.

 

The stand out talk was presented by Dr Abdel-Wahab who provided a stunning series of experiments detailing the role of mutant ASXL1 in myeloid leukemogenesis.  Having originally demonstrated that mutant ASXL1 is oncogenic through loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation, Dr Abdel-Wahab presented recent data on conditional Asxl1-knockout mice.  Deletion of Asxl1 in hemopietic progenitor cells remarkably results in hypo-cellularity and multilineage dysplasia consistent with a bone marrow stem cell defect.  Interestingly, crossing Asxl1-knockout mice with Tet2-deleted mice, that reflects the observation that somatic mutations in ASXL1 and TET2 are often found in myeloid leukemias, resulted in enhanced bone marrow stem cell activity and hypercellularity.  These studies demonstrated the important role of genetically engineered mice to decipher functional interactions between different epigenetic regulators and provided interesting insight into the role of PRC2 in myeloid transformation.

 

In summary the meeting highlighted the diversity and excellent standard of epigenetics research in Japan and the strong focus on translating basic findings into clinical practice.  The symposium served to extend existing collaborations and initiate new ones and by all criteria was an outstanding success.

 

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