Researchers Lisette Anink-Groenen and Pernette Verschure (Swammerdam Institute for Life Sciences (UvA)) and their collaborators from the Hubrecht Institute-KNAW & University Medical Center Utrecht established the cause and consequence of repositioning genomic subdomains for altering the epigenetic composition and gene activity in embryonic stem cells. The results were recently published in the scientific journal Molecular Cell.
The researchers used synthetically integrated binding sites and biochemical technologies to measure genomic interactions. This work shows that a given genomic locus can adopt multiple nuclear locations depending on the recruited protein but repositioning is uncoupled from transcriptional changes in gene activity and epigenetic alterations per se are insufficient for repositioning.
Genome functioning is in eukaryotes largely determined by the organisation of chromosomes in the nucleus. Most physical contacts between gene regulatory elements are considered to take place within defined topology-associated genomic domains. Cell-type-specific nuclear arrangements imply that genomic loci possess an intrinsic flexibility to allow repositioning in response to developmental signals. The link between nuclear localisation, chromatin composition, and gene activity is primarily based on correlations extracted from genome-wide datasets, whereas microscopy studies tracing the location of individual loci show large cell-to-cell variability in nuclear positioning of given loci. The researchers combined synthetic cell-engineered targeting platforms with biochemical genome interaction experiments to bridge this gap in knowledge and establish cause and consequence between nuclear organisation, gene activity, and chromatin composition. This work suggests that trans-associated factors play a major role in chromosome compartmentalisation independent of their local gene activity and epigenetic state cis effect.
Wijchers PJ, Krijger PH, Geeven G, Zhu Y, Denker A, Verstegen MJ, Valdes-Quezada C, Vermeulen C, Janssen M, Teunissen H, Anink-Groenen LC,Verschure PJ, de Laat W. Cause and Consequence of Tethering a SubTAD to Different Nuclear Compartments. Mol Cell. 2016 Feb 4;61(3):461-73. doi: 10.1016/j.molcel.2016.01.001. Epub 2016 Jan 28.