22.8: Current Research Directions

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LADs

(a) 30% of the genome is variable between cell types, how are we able to differentiate these differences

(b) How do lamina and LADs interact? Is there an attractions between LADs and these domains, or is it based on repulsion of the interior

TADs and Other Compartments:

(a) What is the biological basis of compartments, is there some multifaceted component of the compartments?

(b) How do cohesins work? Are cohesin-extrusion pairs enough to explain all domains?

(c) Enhancer-promoter loops are confined to specific domains? Are these dynamic components/are they architectural loops mediated by CTCF?

Other/Miscellaneous:

(a) How do we relate the different chromosomal components (i.e. LADs, TADs, polycomb domain, replica- tion origins, histone modifications, gene expression)?

(b) Evolutionary basis of genomic architecture: was there an evolutional pressure and when did the folding principles emerge?

Did You Know?

This question has (partially) been addressed! In investigating cells that go through multiple rounds of differentiation, it has been observed that some regions will localize to the lamina in the first differentiation but won’t become repressed until the second differentiation!

Body Guard Hypothesis

The body guard hypothesis was proposed in 1975 by Hsu TC. It suggests that inactive DNA is localized to the periphery of the nucleus so that it can ’guard’ the important, active regions of DNA from foreign dangers like viruses or free radicals. Attempts to test the hypothesis by introducing artificial DNA damage have produced circumstantial results, and the question remains open. Single Cell Experiments

It is known that cells retain their original organization after mitosis, as shown by chromosome staining experiments. However, recent experiments have shown that there may be a large difference in organization between the parent and daughter cells. Certain global properties, like chromosome territories, are conserved, but organization at a finer detail may greatly differ. Single cell experimentation is an emerging technique that may be able to address this open question.

FAQ

Q: Has anyone tried increasing expression of a gene in the middle of a LAD? What happened?

A: It’s unclear if there is a specific example of this, however several related studies have been conducted. Researchers have tried to ’tether’ a region of DNA to the nuclear lamina to see if it spontaneously becomes deactivated. However, the results were inconclusive as in half of the cases the region would become inactive and in the other half it wouldn’t! So far these types of manipulations haven’t yielded much, but it was found that if a protein-devoid segment of DNA was digested and mixed with highly purified lamina proteins, the bound fragments reveal a very similar pattern as the LADs. This tells us that lamina directly binds to DNA. However, this does seem to vary between species.