About Us

Our lab is interested in understanding the transcriptional mechanisms that control the differentiation and function of pancreaticinsulin-producing ß-cells. We use this information to gain new insights into the molecular defects that cause different forms of diabetes. This knowledge is also very relevant for the generation of new insulin-producing cells for replacement therapies in Type 1 diabetes.

Mouse genetic analysis of beta-cell regulation

We use genetically modified mice to understand how specific transcriptional regulators control beta-cell differentiation, growth, and function. Using methods such as large-scale gene expression profiling, chromatin immunoprecipitation, and immunoFISH analysis we are deciphering the role of several regulators in the transcriptional networks that guide these processes.

One of our major interests is the study of genes involved in monogenic forms of human diabetes, namely Hnf1a and Hnf4a (also known as MODY3 and MODY1, or Maturity Onset Diabetes of the Young -MODY). Our studies have provided insights into their in vivo function in pancreatic islets, and at the same time uncovered new aspects of the phenotypes of humans with mutations in these genes.

Understanding the epigenome of pancreatic islets

Learning how to generate new beta-cells is a primary goal of regenerative medicine for Type 1 diabetes. This can be potentially achieved through the in vitro differentiation of pluripotent cells, or through transdifferentiation of non-beta cells. Our studies aim at understanding the epigenetic mechanisms that enable and restrict the generation of beta-cells from other cellular sources.

We are also interested in understanding how human genetic variation impacts the epigenome of beta-cells, and the potential implications for the inherited susceptibility of common forms of human diabetes. In a recent study we have created a map of putative regulatory elements in human islets using Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE) coupled to high-throughput sequencing, and showed that sequence variants associated to Tyoe 2 diabetes risk at the TCF7L2 Type 2 locus affect chromatin state. We are currently using a combination of experimental approaches, including large-scale sequencing and functional assays, to dissect the mechanisms whereby specific sequence variants alter diabetes susceptibility.

Regeneration of pancreatic beta-cells

The generation of new beta-cells requires identifying the precursor cells that need to be targeted. Using mouse genetic lineage tracing models we study the cellular origin of new beta-cells that are formed during embryonic development and during adult regeneration. Our recent studies have shown that embryonic pancreatic exocrine ducts give rise to endocrine cells. However, in contrast to widely held beliefs,  adult differentiated exocrine duct cells do not give rise to endocrine cells, even during regeneration.