Analysing the evolution of regulatory chromosomal domains: fundamental units of the genome?

Supervisor: Dr Aleksandr Sahakyan and Professor Doug Higgs

Recent genome-wide data have shown that mammalian genomes may be organised into self-interacting chromatin domains containing various combinations of the fundamental cis-regulatory elements (enhancers, boundary elements and promoters).1-3 It has been suggested that the self-interacting domains represent fundamental building blocks of the genome, which organise the regulatory elements to accurately control gene expression throughout differentiation and development. These self-interacting chromatin domains have been variously described as Chromatin Compartments (A and B), Topologically Associated Domains (TADs), contact domains, sub-TADs, insulated neighbourhoods and frequently interacting regions (FIREs), although the relationships between these domains are not clear.1 Previously, it has been proposed that such domains represent invariant structural features of the genome, which are conserved throughout evolution, but this has not been extensively tested. We have recently characterised and described the self-interacting domains that are found in haematopoietic cells.4,5 We have also studied the domain containing the human and mouse alpha-globin clusters in great detail,6-8 and this serves as a functional model of the self-interacting domain hypothesis.

The aim of this thesis is to perform in-depth computational analyses of the evolution of self-interacting domains and the elements contained within them. This work will test the importance and the generality of the self-interaction domain hypothesis, and unravel its potential role in the evolution of genome architecture. The project would be suitable for candidates coming from diverse backgrounds (biology, chemistry, physics, computer science, engineering) wishing to apply innovative computational approaches to fundamental questions in genome biology.

References:

  1. Gibcus, J. H. & Dekker, J. The hierarchy of the 3D genome. Mol. Cell 49, 773–782 (2013).
  2. Dekker, J., Marti-Renom, M. A. & Mirny, L. A. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat. Rev. Genet. 14, 390–403 (2013).
  3. Bonev, B. & Cavalli, G. Organization and function of the 3D genome. Nat. Rev. Genet. 17, 661–678 (2016).
  4. Davies, J. O. J. et al. Multiplexed analysis of chromosome conformation at vastly improved sensitivity. Nat. Meth. 13, 74–80 (2016).
  5. Davies, J. O. J., Oudelaar, A. M., Higgs, D. R. & Hughes, J. R. How best to identify chromosomal interactions: a comparison of approaches. Nat. Meth. 14, 125–134 (2017).
  6. Hay, D. et al. Genetic dissection of the α-globin super-enhancer in vivo. Nat. Genet. 48, 895–903 (2016).
  7. Mettananda, S. et al. Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia. Nat. Comm. 8, 424 (2017).
  8. Hanssen, L. L. P. et al. Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo. Nat. Cell Biol. 19, 952–961 (2017).

For informal inquiries and more detail, please contact Aleksandr Sahakyan.