Information Flow in Chromatin
A substantial portion of the genome consists of poorly understood but critical sequences called “cis-regulatory elements” (CREs). Unlike protein coding genes, CREs are not transcribed. Instead, they control the genes. The coding sequence of the gene determines what protein is produced, but the CREs that control the gene determine how much protein is produced (if any)and what conditions (such as in what cell type) production occurs. It is these differences in the control of gene activity that are likely responsible for much of the genetic variation between individuals in both appearance and health. Consequently, understanding CREs will be an essential aspect of medicine’s hope to use genomic information to provide precise and personalized treatment.
The best understood CREs are called “promoters,” which are found just in front of the coding sequence. But much of the control depends on more distal CREs such as “enhancers” and “silencers” which may activate, increase, decrease, or inactivate gene expression, possibly by interacting with the promoter. How distal CREs “know” which genes they should control and which they should leave alone remains a central question of biology. Even less understood is how the activity of multiple CREs regulating the same gene is coordinated. Considerable evidence indicates the answer to these questions lies in the cell-type specific three-dimensional (3D) organization of genome, which is believed to be folded in such a manner as to allow certain CREs to interact by physical contact and others to avoid interference by physical separation. Unfortunately, we currently lack the tools to directly observe the physical, 3D organization of genome at the length scale of CREs in single cells, and the ability to measure gene activity concurrently with 3D organization.
Dr. Boettiger’s research aims to understand the 3D genome organization regulating CRE interactions and their role in controlling gene activity by developing new microscopy approaches and combining them with modern genetic methods. His lab is working to develop a super-resolution imaging approach capable of resolving tens to hundreds of individual CREs, associated genes, and intervening sequences in single cells of sectioned embryonic tissue and cultured cells at better than 30 nm resolution. He will apply this approach first to a selection of well-studied loci where the CREs have been identified and the transcribed genes they regulate defined through prior, extensive, genetic work. He aims to identify general principles that regulate physical interactions and shape expression. Because many chronic diseases (such as cancer, psychological abnormality, and dementia) have substantial genetic risk factors that map to potential CREs in the human genome, a better understanding of their interactions may aid development of future treatments and predict disease risk.