3D Chromatin Architecture and conservation of gene regulation

Characterization, rearrangement and conservation of TADs and enhancers

Annotation of functional gene regulatory elements has motivated the understanding of the genome’s spatial organisation. The physical interaction within the nuclear three-dimensional space has emerged as an important factor regulating gene expression. Our work described how the genome partitioned into spatially separated units called Topologically Associating Domains (TADs) that encompass a gene and all its relevant cis-regulatory elements. 

Through analysis of patients with structural variations we could provide first direct evidence for the connection between TADs and gene regulatory domains. This work had direct clinical impact through development of new diagnostic strategies for previously unsolved cases with rare genetic disease, which is now a widely accepted mutation mechanism.

We are interested how and when 3D chromatin architecture affects gene expression and how this compares across species. Many TADs are conserved between species, while the enhancers themselves appear not be conserved (at least in their DNA sequences). We believe that evolutionary informed locus analysis can help to understand the interplay between chromatin structure and function. 

By developing and applying an alignment-based algorithm to identify sequence-diverged but functionally conserved cis regulatory elements based on their genomic position. Our characterization of positionally conserved regulatory elements demonstrates a widespread conservation of enhancers and promoters with highly diverged sequences across large evolutionary distances.