Renewal: MIRA: Epigenetic regulation of genome integrity, environmental interaction, and inheritance

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PROJECT SUMMARY Although the genome is a blueprint for making an organism, the epigenome (modification on the genome without DNA sequence change) governs the functional outcome of genes and ultimately shapes the organism. Epigenetic modification is a conserved and important gene regulatory mechanism and plays quintessential roles in genome integrity, development, environmental responses, and diseases. Despite the large number of correlative studies describing the altered modification patterns in abnormal developmental and pathological tissues, whether they are a cause or a consequence is poorly understood. This proposal dissects the molecular mechanism of epigenetic regulation and functional consequences of epigenome perturbation under developmental and physiological conditions. Specifically, we investigate i) how epigenome reprogramming in response to environmental cues might lead to stress adaptation; ii) how an epigenetic switch regulates developmental phase transition; and iii) how epigenetic modification safeguards the genome integrity. We will further dissect the causal roles of epigenetic marks on gene expression and develop an innovative CRISPR/Cas9-mediated cis- engineering system for epigenome editing. Our approach is highly interdisciplinary making use of the powerful Arabidopsis genetic system, high-throughput proteomics and genomics, live-cell imaging techniques, biochemical and structural tools to tackle mechanistic problems from genome-wide scale to atomic resolution. As we probe basic principles governing epigenetic regulation that are conserved across eukaryotes, the mechanistic knowledge and epigenome technologies acquired from our pioneering Arabidopsis studies will help accelerate progress in deciphering the relevant mechanisms in human. Such knowledge will lead to the development of innovative tools to correct aberrant epigenetic modifications and ultimately enable new applications for medicine and human health.