Research

In an organism like the human body, every cell holds a replica of the individual’s genome. Although all cells share identical genetic information, they can take a variety of shapes and functions to build functional organs and tissue. This is the result of each cell generating proteins only from a specific subset of the ~25,000 genes encoded in the genome. The gene expression process (synthesizing mRNA and protein from a gene) constitutes the basis of differentiation, morphogenesis, and adaptability.

We are interested in understanding how gene expression works, focusing mainly on its first step, transcription (the synthesis of mRNA from a gene encoded in DNA). Evidence shows that transcription is highly regulated: for instance, some genes are transcribed at precise times in the developing embryo; other sets of genes turn on only when the environment changes. However, the order and predictability we observe at the tissue scale contrasts with the random behavior of individual molecules: synthesis of one mRNA copy requires that the transcription machinery components (dozens of proteins) find the precise sequence of DNA where transcription has to start. The randomness of the search process (it occurs through diffusion) coupled with the small number of molecules involved (one or two copies of the DNA) results in natural fluctuations in the RNA levels that can have consequences for the cell’s fate.

One crucial question is how ordered patterns of gene expression can emerge from random dynamics at the molecular scale. We are particularly interested in exploring the role of the vast portions of DNA that do not encode RNA or proteins. Elucidating the mechanisms that drive selective gene expression will better our ability to produce the different cell types needed to regenerate tissues; it will also provide clues to treat diseases in which gene expression is misregulated, such as cancer.

We believe combining approaches from distinct fields is key to linking molecular scale and downstream effects on cells and tissue behaviors. We develop advanced fluorescence imaging to measure the transcription of individual copies of mRNA in living cells. We combine it with genomics and computational biophysics tools to build predictive models.

Specific Projects

Innovative imaging techniques to quantify transcription dynamics in living cells.

Building on our recent technological developments (new fluorescent dyes and photoactivatable dyes, imaging of selected loci,) and insights (the formation of clusters of PolII around transcribing genes), we are extending our exploration of the regulation of transcription at the molecular scale. This requires new creative ways to image and manipulate multiple factors at the gene locus in order to understand how the random, transient binding of factors at the gene can produce long-lasting, productive transcription events. Also of interest are the architecture and dynamics of the DNA itself, in order to understand how chromatin movements constrain or enhance transcription specificity.

Mapping cellular heterogeneity in complex tissue

Tissues are made from distinct cell types that often cooperate to ensure proper function. We are interested in mapping the spatial organization of those cell types within complex tissue in order to better understand those relationships. Cellular heterogeneity plays an important role in tumor development, as different tumor subtypes might compete or cooperate to evade immune defense or chemotherapy. We are characterizing tumor heterogeneity using genomics and 3D imaging in order to identify the causes and effects of cellular heterogeneity in disease.