Project summary Emerging evidence suggests that cells in multicellular organisms can rapidly adapt to changing environmental inputs or metabolic states by dynamically modifying their epigenome and gene expression programs. A major focus in my lab is to investigate the molecular underpinning regulating the interaction between environment and epigenome and how environmental inputs such as oxygen regulate developmental processes or human pathologies through modifying epigenetic marks in the genome. Key epigenetic enzymes such as ten-elven translocation (TET) family of DNA dioxygenase and JmjC-domain-containing histone demethylase directly utilize oxygen as one of their cofactors to modify epigenetic marks on DNA or histone. Depending on their specific microenvironments, cells of the same cellular identity may encounter different oxygen levels and therefore adopt distinct epigenomic and transcriptomic profiles. However, the molecular principles governing environment- epigenome interactions are largely unknown because we do not have methods to precisely map epigenomic responses to continuously distributed environmental inputs and manipulate the epigenome in the context of specific cellular microenvironment. Here we propose to overcome these technical challenges by developing integrated single-cell analysis approach to observe epigenomic and transcriptomic responses to dynamically changing environmental inputs and building a new class of `environment-sensing' synthetic epigenetic enzymes. Armed with these tools, we will have the ability to observe and actively manipulate the interaction between environmental inputs and epigenome `on demand', providing fundamentally new opportunities to study the critical changes in epigenome that are involved in a broad array of biological and pathological processes. !