Epigenetics: plasticity versus inheritability

Our ultimate goal is to understand how we can qualify to be successful multi-cellular organisms. Successful multi-cellular organisms are required to achieve two simple tasks: 1. Cells should be able to alter their fate to generate distinct cell types for different functions, in a process termed differentiation; 2. Cells and their progenies should be able to maintain their fate when differentiation is no more required at the post-mitotic stages or during proliferation.

DNA is unarguably the carrier of genetic information. However, DNA sequence alone cannot explain how hundreds of cell types in a complex multi-cellular organism, such as a human individual can possess distinct transcription programs, while sharing the same genetic information. This is believed to be achieved by fine-tuning our genetic information with a so-called “epigenetic” system. To fulfill the two basic tasks challenging the multi-cellular organisms, epigenetic system must simultaneously offer dual characteristics, “Plasticity & Inheritability”. Plasticity allows the transformation of one genome into hundreds of epigenomes and transcriptomes, whereas inheritability permits the maintenance of every single epigenome and its corresponding transcriptome.

• Mitotic inheritance of histone modification-based epigenetic information

Several histone modifications have been shown to be critical in classic epigenetic phenomena, including Position effect variegation, Polycomb silencing and dosage compensation. However, how newly deposited histones acquire these modifications during/after DNA replication remains unclear. We attempt to address this important question using combinatory approaches by integrating biochemistry, quantitative mass spectrometry and high-throughput sequencing.

• Enzymatic activity regulation of chromatin modifying enzymes

Another important direction in our laboratory is to study the biochemical regulation of chromatin modifying enzymes. Despite the exponentially increasing number of studies about chromatin modifying enzymes, the mechanistic regulation of these enzymes is poorly understood. Therefore, we are interested in understanding the molecular mechanisms behind activation and antagonization of chromatin modifying enzymes. We believe this is an important direction for chromatin biology, not only because of mechanistic insights that can be derived from such studies, but also because a mechanistic understanding will contribute to guided small molecule inhibitor design for chromatin modifying enzymes. This goal is particularly important because many chromatin modifying enzymes, such as histone deacetylases (HDACs) and, more recently, PRC2, are being considered as potential drug targets.