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Scientific Frontline: Extended "At a Glance" Summary: The Dark Genome and Clonal Hematopoiesis
The Core Concept: Clonal hematopoiesis is an age-related condition where mutated blood stem cells expand to form larger populations of blood cells, which can lead to inflammation and disease.
Key Distinction/Mechanism: The two most common mutations driving this condition, DNMT3A and TET2, trigger inflammation through distinct biological pathways. DNMT3A mutations reactivate normally suppressed retrotransposable elements in the "dark genome," while TET2 mutations alter cellular metabolism and oxidative stress pathways.
Major Frameworks/Components:
- Clonal Hematopoiesis: The expansion of mutated hematopoietic stem cells.
- The "Dark Genome": The non-coding portion of the human genome, consisting of over 40% repetitive genetic sequences, including remnants of ancient viruses (retrotransposable elements).
- DNA Methylation: A biological process used to suppress transposable elements; DNMT3A is an enzyme that regulates this process.
- Inflammatory Signatures: DNMT3A mutations are linked to TNF–NFκB and interferon signaling pathways.
Branch of Science: Hematology, Genetics, Bioinformatics, and Immunology.
Future Application: Reactivated retrotransposable elements could serve as biomarkers to identify individuals at a higher risk for cardiovascular disease or blood cancers, and targeting these specific inflammatory pathways could yield new preventive treatments.
Why It Matters: Understanding that different genetic mutations in clonal hematopoiesis cause inflammation via different mechanisms allows for more targeted and personalized approaches to age-related inflammatory diseases.
The study, published in GeroScience, investigated DNMT3A and TET2, the two most common mutations in clonal hematopoiesis, an age-related condition in which mutated blood stem cells expand and form larger populations of blood cells.
Researchers found that large DNMT3A-mutant clones showed widespread reactivation of normally suppressed retrotransposable elements—parts of the "dark genome" that include remnants of ancient viral sequences. In contrast, TET2 showed lower activity in the dark genome but changes in pathways associated with cellular metabolism and oxidative stress.
He added: "In the future, we hope to establish whether targeting these specific inflammatory pathways could provide new ways to prevent or treat disease in people with clonal hematopoiesis."
Clonal hematopoiesis occurs when a mutation in a hematopoietic stem cell results in the expansion of a population of blood cells carrying the same mutation. It is associated with adverse health outcomes, including blood cancers, cardiovascular disease, and atrial fibrillation, where the heartbeat is irregular or abnormally fast.
DNMT3A and TET2 both help regulate which parts of our DNA are active or suppressed. The researchers therefore investigated whether mutations in these genes could affect the activity of transposable elements—stretches of DNA that are normally kept switched off.
More than 40% of the human genome, called the "dark genome," consists of repetitive genetic elements known as transposable elements, including a major group called retrotransposable elements (RTEs). These include remnants of ancient viruses that became embedded in our ancestors' DNA millions of years ago. These sequences are normally kept tightly suppressed, including through a process called DNA methylation.
In this study, the researchers analyzed blood samples from 68 people, with 56 having CH and 12 acting as non-CH controls. The participants were all over 50 and undergoing hip replacement surgery.
They focused on two of the most common mutations found in clonal hematopoiesis—DNMT3A and TET2—to understand why these mutations cause inflammatory changes.
DNMT3A is an enzyme involved in controlling DNA methylation. If a blood stem cell acquires a damaging DNMT3A mutation, this system can become disrupted. The researchers found evidence that this is associated with RTEs becoming activated, particularly when the population of blood cells carrying the mutation was large. This reactivation was associated with inflammatory pathways, including TNF–NFκB and interferon signaling.
In contrast, TET2-mutant cells showed lower levels of retrotransposable-element activity and lacked the same dark-genome-associated inflammatory signatures. Instead, they showed changes in pathways associated with cellular metabolism and oxidative stress, suggesting inflammation may arise through a different mechanism.
The findings therefore indicate that although both mutations are associated with inflammation, the underlying biological processes may be different.
The researchers believe that RTE activation could eventually be used as a biomarker. If future experiments demonstrate that RTE activation directly contributes to inflammation, targeting this pathway could also potentially provide a new approach to treatment.
Funding: This study was funded by Celgene, a Bristol Myers Squibb company, through a partnership with King's Health Partners.
Published in journal: GeroScience
Authors: Maroof Hasan, Sylvia Durandeau, I. Richard Thompson, Hanae Roussotte, Yi-Ting Tsai, Nogayhan Seymen, Sila Gerlevik, Nicholas Bianchini, Khadijeh Alishah, Merilyn M. Albuquerque, Jen Lewis, Laarni Bonganay, Niels Asger Jakobsen, Bernd Zeisig, Sheeba Irshad, Paresh Vyas, Eric C. W. So, Alfredo Iacoangeli, Xuesen Zheng, Sarah Mackie, Kai Yi Mok, Viktoria Uksaite, Louis-Francois Handfield, Giorgio Napolitani, James Carmichael, Ghulam J. Mufti, Anita K. Gandhi, Rajasekhar N. V. S. Suragani, Lynn Quek, and Mohammad M. Karimi
Source/Credit: King’s College London
Edited by: Scientific Frontline
Reference Number: bio092326_01
