Regulation of canonical and non-canonical substrates of histone lysine methyltransferases

PROJECT SUMMARY Protein lysine methylation is a post-translational modification (PTM) that neutralizes the positive charged side chain and modulates protein functions in many key biological events. In metazoans, somatic cells displaying distinct cellular phenotypes are originated from one zygote and contain the identical sequence of DNA. Upon differentiation, transition of cell fate is initiated by lineage transcription factors and a cell identity is stabilized by epigenetic factors that define a chromatin state. Distinct histone lysine methylation is central to active or repressive chromatin formation. Dysregulation of this process often leads to pathogenic conditions such as developmental disorders or cancer. Once an epigenetic state is established, cells need to faithfully recapitulate the steady state in mitosis in order to safeguard cell identity and prevent developmental dysregulation and oncogenic transformation. The epigenetic inheritance is a new research discipline undergoing rigorous investigations. Despite that significant advancement has been achieved to decipher the mechanisms of repressive chromatin inheritance, how active chromatin is inherited, involving temporo-spatial regulations of histone lysine methyltransferases, still remains elusive. In addition to histones, histone lysine methyltransferases also catalyze non-histone methylation events, whose importance is emerging in the context of early development. However, there is a lack of systematic investigation of these non-canonical substrates and how they critically regulate distinct biological processes. In this proposal, we will address these key knowledge gaps by interrogating the mechanistic questions in active chromatin inheritance and develop a new approach to investigate non-canonical methylation events by histone lysine methyltransferases. We expect to establish new research platforms and advance our understanding towards methylation biology.