Design Principles of Gene Expression in Mammalian Tissues

We develop single molecule approaches to quantify promoter states, transcription rates and mRNA degradation rates in intact mammalian tissues. We are also investigating the patterns of intra-cellular compartmentalisation of mRNA in epithelial tissues.

Design Principles of Mammalian Glucose Homeostasis

Glucose homeostasis is a central feature of mammalian metabolism. Our bodies maintain remarkably constant glucose levels in spite of vast variations in the rates of glucose influx and clearance. This physiological goal is achieved through the coordinated secretion of the hormones insulin and glucagonby the pancreatic islets of Langerhans. Inter-cellular interactions within the intact islet seem to be critical for achieving robust response to glucose fluctuations and perturbations in these interactions may play a significant role in diabetes. We use mathematical modeling and in-situ measurements to characterize the intra-islet interaction network and to uncover the functional significance of the islet architecture.

Spatial division of labor in the mammalian gut

Our intestines are lined with a single layer of epithelial cells that forms a highly folded structure. Cells are constantly emerging from deep stem-cell harboring crypts and migrate along the walls of protrusions called villi until they reach their tips, where they are shed off into the lumen. Using spatially resolved single cell RNA sequencing, we found that epithelial cells constantly change their function as they migrate along the villi walls, specializing in distinct tasks at different villi heights. We study the design principles of these zonated expression programs, the mechanisms that shape them and their changes in diverse metabolic disease.

Single Cell Heterogeneity in the Mammalian Liver

The mammalian liver performs critical functions for maintaining metabolic homeostasis. These functions are carried out by hepatocytes operating in repeating anatomical units termed liver lobules. The liver lobule is polarized by centripetal blood flow, which creates gradients of nutrients, hormones and oxygen. In line with this graded microenvironment hepatocytes at different lobule coordinates sub-specialize in distinct functions. We study how this spatial division of labor within the liver lobule can serve to bring about optimal tissue function in face of these long-range constraints. An additional puzzling feature of the mammalian liver is its polyploidy. In contrast to most tissues in our body, which are composed of diploid cells, the liver consists of a mixture of diploid, tetraploid and octoploid cells. We are studying the physiological significance of liver polyploidy using single molecule imaging methods.