Hansen Lab

The Hansen Lab is interested in understanding the interplay between genome organization and regulation of gene expression in mammals. Towards this goal, we develop new experimental and computational tools for following these biological processes inside living cells with single-molecule resolution dynamically over time. And we integrate these approaches with traditional genomic, biochemical and molecular biology approaches. We then apply these tools to understand how genome organization and gene expression is regulated during development and differentiation, and how dysregulation of these processes causes disease, with a particular focus on cancer and developmental diseases. By deciphering the biophysical principles underlying genome organization, our goal is reach a predictive understanding that will permit computationally-guided de novo design of spatial domains with desired regulatory functions, with applications in synthetic biology. Ultimately, this may  allow us to correct genome misfolding in disease.

We are committed to open, robust and reproducible science, where we go after the most important questions in a highly collaborative manner. We are also committed to maintaining an inclusive environment, where everyone feels welcome regardless of background.

Proper regulation of gene expression is essential for nearly all biological processes, including the remarkable ability of a single cell to develop into a fully formed organism. And dysregulation of gene expression underlies many diseases. However, understanding gene regulation in mammals comes with a big challenge: Mammalian genomes are enormous. They contain tens of thousands of genes and hundreds of thousands of enhancers. And enhancers, DNA-elements that activate gene expression, can be hundreds of kilobases or even megabases away from the genes that they control. So, how does the cell ensure that the right enhancer contacts the right gene to establish cell-type specific gene expression programs?
It is becoming clear that we can only understand mammalian gene regulation if we understand the 3-dimensional folding of the genome, which controls which enhancer talks to which gene promoter. Specifically, architectural proteins - including CTCF and cohesin - fold the genome into spatial domains by forming chromatin loops. By constraining enhancer-promoter contacts, these domains are thought to regulate gene expression. Moreover, genome misfolding through domain disruption can cause cancer by inducing aberrant enhancer-promoter contacts, which results in oncogene activation. Powerful static snapshot approaches such as Hi-C have revealed the existence of these domains and chromatin loops. However, understanding how loops and domains form, persist, dissolve, and function requires an ability to visualize them and dynamically follow them from “birth-to-death”. We develop experimental, super-resolution imaging and computational technologies for visualizing the dynamics of chromatin loops and the key proteins that regulate looping at the single-molecule level in living cells. And we then then apply these tools to address important biological questions: (1) What are the molecular mechanisms that regulate chromatin looping? and (2) How is chromatin looping and transcription regulated during development and dysregulated in disease?

Ultimately, our long-term goal is to take an engineering approach and integrate synthetic biology and 3D genome biology. By deciphering the biophysical principles underlying genome organization, we aim to reach a predictive understanding that will permit computationally-guided de novo design of spatial domains and loops with defined enhancer-promoter contacts and gene expression outputs. This may ultimately allow us to correct genome misfolding in disease.

The approach -- Most biological processes are inherently dynamic and stochastic. Yet, most methods used in biology are time- and/or ensemble-averaged. But to understand a dynamic process, we must use methods that capture its dynamics. For example, if A always occurs just before B, there is a good chance that A is causal for B. Our approach is therefore to develop "birth-to-death" approaches, where we can follow biological processes from beginning to end. That is, we develop new experimental, microscopy and computational methods for tracking these processes at the single-molecule level inside living cells with millisecond and nanometer resolution in time and space (e.g. movie on right). In the case of chromatin looping and enhancer-promoter contact, this means developing new tools that allow us to follow loops inside living cells as they form, persist, function and eventually dissolve.

Following individual molecules inside living cells over time is hard. It requires: 1) new genome-editing and labeling methods; 2) new microscopes for high-resolution imaging; 3) new computational methods for rigorously analyzing and making sense of the data. We therefore take an interdisciplinary approach where biologists, engineers, and physical scientists work closely together to achieve these goals. And we integrate these approaches with traditional methods like biochemistry, genomics and molecular biology in a question-focused manner.