Intricate human physiological features such as the immune system require exquisite formation and timing to develop properly. Genetic elements must be activated at just the right moment, across vast distances of genomic space.

"Promoter" areas, locations where genes begin to be expressed, must be paired precisely with "enhancer" clusters, where cells mature to a targeted function. Faraway promoters must be brought in proximity with their enhancer counterparts, but how do they come together? When these elements are not in sync, diseases such as leukemia and lymphoma can result. How does this work?

Biologists believe they have the answer. Calling it the "big bang" of immune cell development, the researchers made their discovery within previously overlooked stretches of DNA located between genes. The results, published in the journal Cell, researchers carried out genomic studies and genetic experiments in mice, and found that the ignored areas, known as "non-coding" DNA, activate a change in the 3D structure of DNA that brings promoters and enhancers together with stunning accuracy.

Senior researcher describes the mechanism as somewhat like a stiff wire -- with enhancers and promoters on either end--that's bended together into a loop and anchored in place. Enhancers and promoters, once distantly separated, are now repositioned in close proximity to initiate the development of immune system building blocks known as T cells.

It is now established that Bcl11b specifies T cell fate. Authors demonstrate that in developing T cells, the Bcl11b enhancer repositioned from the lamina to the nuclear interior. They identified a non-coding RNA named ThymoD (thymocyte differentiation factor) relocalized the Bcl11b enhancer.

ThymoD-deficient mice displayed a block at the onset of T cell development and developed lymphoid malignancies. Authors found that ThymoD transcription promoted demethylation at CTCF bound sites and activated cohesin-dependent looping to reposition the Bcl11b enhancer from the lamina to the nuclear interior and to juxtapose the Bcl11b enhancer and promoter into a single-loop domain.

These large-scale changes in nuclear architecture were associated with the deposition of activating epigenetic marks across the loop domain, plausibly facilitating phase separation. These data indicate how, during developmental progression and tumor suppression, non-coding transcription orchestrates chromatin folding and compartmentalization to direct with high precision enhancer-promoter communication.

"Nature is so clever. We think of the genome as an unstructured strand but in fact what we are seeing is a highly structured and meaningful design," said the senior author. "The process of architecture remodeling we've described allows the enhancer and promoter to find each other in 3D space at precisely the right time. The beauty is that it's all very carefully orchestrated. We have seen one example but there are likely many others all occurring at the same time when cells are moving along the developmental pathway-that's kind of amazing."

While the researchers concentrated on T cells, they believe this mechanism may be unfolding throughout the animal and plant kingdoms.

When the mechanism fails, T cell development falters and diseases such as lymphoma and leukemia result. Senior author says the results show how the forgotten strands of DNA suppress the development of leukemia and lymphoma.

"The implications of these results are not only how normal T cells develop, but that tumor suppression is regulated through this mechanism, at least in part," said the senior author. "Ultimately we may be able to fix mutations associated with disease and these forgotten strands of DNA."

http://www.cell.com/cell/fulltext/S0092-8674(17)31050-4