Regulation of Transcription and Looping in Development and Disease

The main experimental system is mouse embryonic stem cells. When a stem cell divides, it needs to maintain its transcriptional program: pluripotency genes should be ON and differentiation genes should be OFF. Long-range enhancer-promoter communication plays a key role in the maintenance of such transcriptional programs. But when cells differentiate (e.g. from a stem cell to a neuron), cells need to establish completely new transcriptional programs and long-range enhancer promoter contacts appear to be especially important in these cases.

So, how does this work? Questions motivating these efforts include:
(*) How and to what extent does 3D genome organization and looping regulate gene expression during development?
(*) What are the molecular mechanisms through which cell-type specific regulation is achieved?
(*) How are the dynamics regulated during development?

We are pursuing these questions using both in vitro stem cell differentiation as well as organoid models - both of which are accessible to high-resolution imaging.
For the same reason that enhancer-promoter looping can activate a developmental gene to induce differentiation, aberrant enhancer-promoter looping (e.g. through mutation of CTCF, cohesin or their binding sites) can cause disease. After all, many diseases are caused by expressing the wrong gene at the wrong time. Dysregulation of chromatin looping appears to occur especially frequently in cancer and we are interested in applying our imaging approaches to elucidate the molecular mechanisms through which dysregulation of looping causes cancer.