Molecular Mechanism of TET-mediated Gene Regulation

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PROJECT SUMMARY/ABSTRACT DNA cytosine methylation is a central epigenetic modification in mammalian cells. Aberrant DNA methylation has been linked to gene dysregulation and genomic instability, resulting in cancer and other diseases. Ten- Eleven Translocation (TET) is the essential enzyme family responsible for DNA demethylation to ensure the proper maintenance of the methylome. TET enzymes oxidize 5-methylcytosines (5mC) into mainly 5- hydroxymethylcytosine (5hmC), an intermediate for DNA demethylation and a potential epigenetic mark. Germline deficiency of TET2 is associated with immunodeficiency and childhood cancers. Notably, TET2 is one of the most frequently mutated genes in hematological cancers, demonstrating the importance of TET in multiple biological processes. We and others have shown that TET enzymes are essential for cell differentiation by regulating super-enhancers and inducing the expression of lineage-specific genes. However, the mechanism by which TET enzymes facilitate the permissive chromatin environment for gene activation remains unclear. The long-term goals of the research program are: (1) to comprehensively understand how TET enzymes and 5hmC promote chromatin accessibility; (2) to investigate the crosstalk between TET and histones; (3) to understand the consequences of temporary perturbation of epigenome. To accomplish these goals, we will use precision epigenome editing to manipulate and monitor epigenetic modifications of cis- elements regulated by TET and DNA methylation. We will develop novel animal models to study the impact of acute and reversible TET deficiency and a sequencing method to map multiple DNA modifications and chromatin accessibility simultaneously on a single DNA molecule. Our research will provide crucial mechanistic insights into how TET and DNA modifications regulate gene expression and cell differentiation. Our findings will potentially identify genes involved in immunodeficiency and cancer, providing an opportunity to develop targeted treatments.