We are interested in the mechanisms that underlie epigenetic memory of cell fate decisions. In metazoans, the organization of genomic DNA into chromatin provides an opportunity to tightly regulate gene accessibility and differential readout required for cellular differentiation. In particular, diverse chemical modifications of nucleosomes and DNA fundamentally shape chromatin structure and are thought to reinforce maintenance of expression states through genome replication, independently of the initial stimulus.
The dynamic regulation of differential chromatin modification states and their contribution to the epigenetic inheritance of cell identity remains enigmatic. We use synthetic biology approaches in mouse stem cells to manipulate chromatin modifications and study their dynamics and inheritance.
We are fascinated by the specialization of distinct cell types from the totipotent zygote and pluripotent somatic stem cells. How do epigenetic mechanisms establish, maintain and propagate distinct gene expression programs? How are they regulated? How do they go awry in disease? Can they be targeted for therapeutic intervention?
We want to illuminate the epigenetic mechanisms that establish and maintain stable gene expression states. Ultimately, we aim to unravel the crosstalk between epigenetic regulation and cell plasticity.
In addition to genetic and biochemical analyses of chromatin regulatory activities, we apply innovative biosynthetic technologies which enable reversible targeting to directly interrogate the function in transcriptional gene regulation in vertebrate cells. By integrating small molecule-dependent control with precise biochemical analyses of chromatin changes, we systematically resolve the contributions of different modifying-activities to form repressive chromatin structure, as well as to initiate and propagate gene silencing. This reductionist approach to recapitulate complex chromatin landscapes offers a unique entry point to use genetic and pharmacological tools to dissect the mechanism of epigenetic regulation. In addition, kinetic measurements at high temporal resolution enable mathematical modelling of complex histone modification dynamics and patterns.
We aim to identify and understand the regulatory feedback mechanisms that facilitate robust maintenance of gene expression states through the massive chromatin reorganisation entailed by genome replication. As key regulators of this process have been implicated in tumorigenesis, elucidating the molecular underpinnings of normal and aberrant chromatin regulation is critical on the path to developing effective clinical therapies.
Hathaway, NA., Bell, O., Hodges, C., Miller, EL., Neel, DS., Crabtree, GR. (2012). Dynamics and memory of heterochromatin in living cells. Cell. 149(7):1447-60
Bell, O., Tiwari, VK., Thomä, NH., Schübeler, D. (2011). Determinants and dynamics of genome accessibility. Nat Rev Genet. 12(8):554-64
Bell, O., Schwaiger, M., Oakeley, EJ., Lienert, F., Beisel, C., Stadler, MB., Schübeler, D. (2010). Accessibility of the Drosophila genome discriminates PcG repression, H4K16 acetylation and replication timing. Nat Struct Mol Biol. 17(7):894-900