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Editing the Epigenome: Plasticity and Memory of Chromatin Structure

 

Principal Investigator: Oliver Bell

In metazoans, packaging of genomic DNA into the nucleosomal protein scaffold of chromatin provides an opportunity to tightly regulate accessibility and readout of the genetic information. In particular, chemical modifications of nucleosomes and DNA have emerged as important determinants of genome accessibility. However, the dynamic regulation of chromatin state and its contribution to epigenetic inheritance of gene expression has remained enigmatic and a key challenge in the field of chromatin biology.

We have developed a novel technology that allows for rapid addition and removal of chromatin regulatory activities to a gene locus in any murine cell type. The Chromatin in vivo Assay (CiA) employs small molecules, which simultaneously bind two distinct peptide domains to induce dimerization between a chromatin modifier and a DNA binding protein. The CiA approach provides high temporal control allowing us to study the kinetics and epigenetic memory of histone modifications at single cell resolution. Kinetic measurements will enable mathematical modeling of complex histone modification dynamics and patterns which will lead to a better understanding of the mechanisms involved in establishment and maintenance of stable gene expression states. Further, the CiA system provides a powerful screening approach to identify novel components as well as modulators of chromatin regulatory pathways. These studies aim to unravel the crosstalk between epigenetic regulation and cell plasticity and ultimately help to incorporate epigenetic regulation into current transcriptional regulatory models.

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