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 3D organization of the genome. While interactions between regulatory elements and transcribed elements are long-range, they still occur only on the same chromosome (in cis) and are not known beyond the scale of a couple megabases. This is one line of evidence suggesting physical proximity of the elements is necessary for regulatory interaction. Moreover, if one regulatory element is artificially inserted immediately next to a transcribed element that it does not normally regulate, it will generally start to modify transcription, indicating that physical proximity is generally sufficient for regulatory interaction.  Nonetheless, it is not well understood how the genome is organized in the 3D environment of the nucleus to promote the correct interactions and avoid potentially deleterious ones or what mechanisms regulate this organization.

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.

3d_genome

Visualizing cis-regulation

Visualizing cis-interactions in vivo

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Spatially resolved transcriptomics

MERFISH

lasers1

super-resolution microscopy of the 3D genome

3D Genome Structure

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