Dr Tomoyuki Sawado

Stem Cells and Chromatin Team
Evaluation of the Link Between Epigenetic Inheritance Levels During DNA Replication and Clonal Heterogeneity

A fundamental question in biology is how a stem cell population gains and balances its self-renewal capability and multi-lineage potential. Evidence suggests that stem cells and progenitors display a significant heterogeneity, and the presence of distinctive subpopulations enable stem cells/progenitors to respond to various differentiation signals while retaining their self-renewal potential. Importantly, this heterogeneity is found in a number of defined stem cell populations that are genetically identical, implicating the involvement of epigenetic regulation in elevating population diversity.  

Our working hypothesis is that inaccurate epigenetic inheritance during DNA replication results in clonal heterogeneity. This is based on the assumption that distinct epigenetic states on two replicated sister chromatids are independently delivered to daughter cells during mitosis, generating asymmetric daughter cells.

During differentiation, whether or not a cell undergoes self-renewal or differentiation is determined by intrinsic and/or external signals that allow a small pool of pluripotent stem cells to generate a large number of differently committed progenitors while not compromising the size of the stem cell compartment. In theory, this process could be achieved by a combination of four mechanisms: i) symmetric divisions of stem cells or progenitors as needed to maintain their populations; ii) symmetric divisions of cells followed by a post-mitotic determination of asymmetric cell fates; iii) polarity formation in mother cells followed by asymmetric divisions; iv) and symmetric divisions that lead to the generation of two identical differentiated cells. We believe that differing levels of accuracy of the epigenetic inheritance during DNA replication would affect the balance among these division modes, thereby altering the levels of clonal heterogeneity.

Importantly, shifting the balance of division modes may also be a hallmark of oncogenic transformation of stem cells and progenitors. For example, the loss of factors that promote asymmetric divisions can result in: hyperproliferation, differentiation deficiency and failure to exit the cell-cycle. In addition, mislocalisation of polarity regulators and cell-fate determinants during divisions, leads to a failure to suppress oncogenes such as Myc. It is possible that error-prone epigenetic inheritance may not only increase the level of intra-tumour heterogeneity that prevents successful clinical intervention, but may also increase the risk of hyper-proliferation that may trigger oncogenic transformation.

Although the link between epigenetic inheritance levels during DNA replication and the resultant phenotypes of daughter cells is a fascinating issue, the relationship between these two events has not yet been studied. In our team, we address this question through several different approaches.

As the leader of Stem Cells and Chromatin Team, Dr Sawado’s research attempts to understand epigenetics, - the biological phenomena where the ‘on’ or ‘off’ state of a gene is determined by mechanisms other than a change in the DNA sequence. The goal of his team is to clarify how epigenetic information is propagated, and how the fidelity of propagation is related to the cell population diversity, which is commonly observed in both normal stem and cancer cells. Evaluating the link between epigenetics and cell population diversity will help reveal how normal stem and cancer cells acquire new characteristics overtime in a living organism.

Dr Sawado obtained his PhD from the Tokyo University of Science (Japan) in 1999. He joined the Salk Institute for Biological Studies (USA) in 1999, and then the Fred Hutchinson Cancer Research Center (USA) in 2000 as a Postdoctoral Fellow.

During his postdoctoral years, Dr Sawado studied how specific DNA elements epigenetically regulate gene expression using both in vitro and mouse systems. He developed a novel system to analyse epigenetic regulation using heterozygous mice (mice possessing two different forms of a particular gene). He also established a novel method to purify and fractionate red blood cells using magnetic beads on a large scale. He joined the Institute of Cancer Research (ICR) in 2008 to start his own research team.

Dr Sawado has received several prestigious awards including the following: Naito Foundation Award, Uehara Memorial Fellowship Award, Japan Science Technology Corporation (JST) Special Fellow Award, American Society of Hematology (ASH) Scholar Award and Leukemia Lymphoma Socieity (LLS) Career Development Program Award.

Outside of work, Dr Sawado performs the piano and flamenco guitar. He is also interested in musicology and historic recordings, and was closely involved in Dr Kevin Bazzana’s research project on a Hungarian pianist and composer Ervin Nyiregyhazi, leading to the award-winning book entitled’Lost Genius: The Curious and Tragic Story of an Extraordinary Musical Prodigy’.