Forgotten strands of DNA initiate the development of immune cells

September 21, 2017
Schematic diagram showing how a subset of immune cells, named DN2a T cells, mature into DN2b T cells. The maturation of this step is among the earliest in immune cell development and is controlled by the forgotten DNA strands that allow the genome to change its architecture to induce the 'Big Bang' of T cell development. In the absence of the "forgotten strands" DN2a cells fail to mature and ultimately after accumulating additional mutations become malignant T cells also named leukemias or lymphomas. Credit: UC San Diego

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 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 at the University of California San Diego 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 September 21 edition of the journal Cell, were led by Takeshi Isoda in Cornelis Murre's laboratory in UC San Diego's Division of Biological Sciences.

Through genomic studies and genetic experiments in mice, the scientists 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. Murre 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.

Detailed description how the 'forgotten strands' change the nuclear location and three-dimensional architecture of a genetic locus to control the development of immune cells and suppress the development of leukemia and lymphoma. ThymoD indicates the 'forgotten strands'. Bcl11b refers to the genetic locus that orchestrates the development of immune cells and suppress the development of leukemia and lymphoma. Credit: UC San Diego

"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 Murre. "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 Murre and his colleagues 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. Murre 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 Murre. "Ultimately we may be able to fix mutations associated with disease and these forgotten strands of DNA."

Explore further: Preventing too much immunity

Related Stories

Preventing too much immunity

December 27, 2016
Scientists at the Immunology Frontier Research Center (IFReC), Osaka University, Japan, report a new molecular mechanism that could explain the cause of some autoimmune diseases.

DNA looping architecture may lead to opportunities to treat brain tumors

September 11, 2017
The discovery of a mechanism by which normal brain cells regulate the expression of the NFIA gene, which is important for both normal brain development and brain tumor growth, might one day help improve therapies to treat ...

New insights into T-cell acute lymphoblastic leukaemia development

May 30, 2017
A research team from the National University of Singapore (NUS) led by Assistant Professor Takaomi Sanda, Principal Investigator from the Cancer Science Institute of Singapore and Department of Medicine at NUS Yong Loo Lin ...

Blunting CRISPR's 'scissors' gives new insight into autoimmune disorders

August 30, 2017
Each one of our cells has the same 22,000 or so genes in its genome, but each uses different combinations of those same genes, turning them on and off as their role and situation demand. It is these patterns of expressed ...

Recommended for you

Researchers find evidence of DNA damage in veterans with Gulf War illness

October 19, 2017
Researchers say they have found the "first direct biological evidence" of damage in veterans with Gulf War illness to DNA within cellular structures that produce energy in the body.

Researchers drill down into gene behind frontotemporal lobar degeneration

October 19, 2017
Seven years ago, Penn Medicine researchers showed that mutations in the TMEM106B gene significantly increased a person's risk of frontotemporal lobar degeneration (FTLD), the second most common cause of dementia in those ...

New clues to treat Alagille syndrome from zebrafish

October 18, 2017
A new study led by researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies potential new therapeutic avenues for patients with Alagille syndrome. The discovery, published in Nature Communications, ...

Genetic variants associated with obsessive-compulsive disorder identified

October 18, 2017
(Medical Xpress)—An international team of researchers has found evidence of four genes that can be linked to obsessive-compulsive disorder (OCD). In their paper published in the journal Nature Communications, the group ...

An architect gene is involved in the assimilation of breast milk

October 17, 2017
A family of "architect" genes called Hox coordinates the formation of organs and limbs during embryonic life. Geneticists from the University of Geneva (UNIGE) and the Swiss Federal Institute of Technology in Lausanne (EPFL), ...

Study identifies genes responsible for diversity of human skin colors

October 12, 2017
Human populations feature a broad palette of skin tones. But until now, few genes have been shown to contribute to normal variation in skin color, and these had primarily been discovered through studies of European populations.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.