Research

The Boettiger lab aims to understand how long-range interactions between non-consecutive parts of the genome are regulated to control gene expression. Such interactions between cis-regulatory elements (such as enhancers and promoters) are essential for all developmentally regulated genes and lies at the core of cell differentiation. Differences in CRE activity and CRE interactions are likely responsible for much of the genetic variation between individuals in terms of both appearance and health, as the transcribed sequence of genes is highly conserved. While tools for identifying CREs and testing their behaviour in isolated context have increased in recent years, progress in understanding information flow between CREs and transcription elements (TEs) has been limited for want of tools to directly visualize interphase chromatin nano-structure, a lack of studies correlating structure and expression at single cell level and a lack of sufficient studies editing CREs to test their causal effects on 3D structure.

Our Interests

We seek to understand the control of gene expression. Differences in gene expression underlie the tremendous variety of cell types in our bodies and account for most of the innate differences between you and me or between me and chimpanzee. These differences are encoded in the non-transcribed parts of our genome called cis regulatory elements, regions that bind proteins (in a sequence dependent manner), which regulate transcription of surrounding genes. Surprisingly, these regulatory elements can be very far away (in linear sequence) from the transcribed elements they control, frequently tens to hundreds of thousands of basepairs apart.  A major direction in the lab is to understand how such long-range interactions occur, how they achieve target specificity, and how they may be reprogrammed by alterations to the genome sequence.

We believe the answers to these questions require understanding the 3-D organization of the genome. While interactions between regulatory elements and genes are long-range, they still occur only on the same chromosome (in cis) and are not known beyond the scale of a couple of megabases, suggesting physical proximity of the elements is necessary for regulation. Moreover, if a regulatory element is artificially placed directly adjacent to a new promoter that it does not normally regulate, it will typically activate transcription from that promoter, indicating that physical proximity is generally sufficient for regulation.  The genome must therefore be folded in such a way to allow communication between all the sequences that need to interact and to segregate those that should not interact.  What this 3-D organization looks like, how it is established, how it changes over development, and what the consequences are for the control of gene expression are all poorly understood questions, which our lab is working to answer.

Our Tools

To answer these questions we need new tools.  Our lab is engaged in using developing and combining new technologies to enable this research, including:

  • super-resolution imaging
  • single molecule microscopy
  • genetic engineering
  • next generation sequencing approaches
  • mathematical and biophysical modeling

See our research projects below for some examples of this approach in action.

Visualizing cis-regulation

Visualizing cis-interactions in vivo

Spatially resolved transcriptomics

MERFISH

super-resolution microscopy of the 3D genome

3D Genome Structure

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