How telomere defects can cause inflammatory diseases

All of the DNA in our cells is organized into complex structures called chromosomes, which consist of our genetic material coiled around many proteins. The chromosome structure helps to condense and protect the DNA. At each end of every chromosome is a long sequence of repetitive DNA called a telomere.

“Telomeres are a kind of cap-like structure that protects the integrity of our genome,” says postdoctoral fellow Deepavali Chakravarti, Ph.D. “Our chromosomes are extremely vulnerable to damages, and telomeres provide important protection to prevent damage and preserve chromosomal integrity.”

Chakravarti likens this to an open-ended tube with stoppers on either end. The tube contains very precious material – our DNA – and the telomeres are essential for keeping the system intact. So, when telomeres are lost or become too short, there can be significant health effects.

Working in the laboratory of Ron DePinho, M.D., Chakravarti recently discovered how telomere dysfunction can cause increased inflammation in the intestine, possibly leading to conditions such as inflammatory bowel disease and colorectal cancer. Their research was published in Nature Communications.

Preserving telomere length is important for health

Each time a cell divides, a small portion of the telomere DNA is normally lost. Therefore, telomeres become shorter as we age. There are mechanisms in place to preserve telomere length, including a group of proteins called the “shelterin complex” that is part of the cap structure.

Inherited mutations in shelterin proteins or other telomere-related genes can lead to premature telomere shortening and a variety of health conditions known as telomeropathies.

This group of rare diseases includes a form of bone marrow failure called dyskeratosis congenita, as well as aplastic anemia, idiopathic pulmonary fibrosis and liver fibrosis.

“All of these diseases were found to be associated with telomere dysfunction through sequencing for mutations in the patients,” says Chakravarti. “Common to all of these diseases is signs of increased aging in the tissues, associated with the shortened telomere length.”

Also commonly associated with telomere dysfunction are inflammatory diseases, such as kidney fibrosis, liver cirrhosis and inflammatory bowel disease. Many of these conditions can increase an individual’s risk of cancer. Not all of them have associated genetic mutations, but they all display shortened telomeres as a hallmark of the disease.

Discovering a link between telomeres and inflammation

There have long been correlations between telomere dysfunction and inflammation, explains Chakravarti, but previously it was unclear whether one was a direct cause of the other. To work toward answering this longstanding question, she studied mice with telomere dysfunction in their intestinal cells.

As expected, those mice had shorter telomeres and increased intestinal inflammation. However, restoring telomere function genetically reversed both of these conditions. This suggests that the inflammation is driven by the disruption of telomeres.

Through their research, Chakravarti and her colleagues observed similar gastrointestinal inflammation in samples from pediatric patients with telomere defects. Seeing this degree of inflammation in young patients further suggests that telomere disruption is the cause.

The research team went on to work out the precise molecular mechanism behind this process. Like a cellular domino effect, telomere dysfunction leads to activation of the ATM protein. This in turns leads to activation of a protein called YAP1, which controls expression of pro-IL-18, an “immature” form of the inflammatory signal IL-18. Pro-IL-18 is processed by Caspase-1 into IL-18 and goes on to stimulate inflammation and recruit immune cells.

Toward treatments for inflammatory conditions

Knowing how telomere dysfunction drives inflammation provides a number of possible therapeutic targets to treat inflammatory diseases caused by telomere defects. In fact, the researchers showed that blocking ATM, YAP1 or Caspase-1 can reduce inflammation in the mice from this study.

However, this is a complex process with many other pathways involved that have yet to be discovered.

“This paper is the first demonstration of how telomere dysfunction activates inflammation,” says Chakravarti. “However, what we’ve discovered is only the tip of the iceberg. Telomere dysfunction is likely activating several factors, which in turn stimulate many other pathways.”

For example, there appears to be an important dynamic between inflammation and the gut microbiome, the bacteria living within our gastrointestinal system. In the same mouse models with telomere dysfunction, treating with antibiotics was also capable of reducing the intestinal inflammation.

Although there is much work left to better understand this process, these findings provide a starting place for future studies that explore preventive or therapeutic strategies for inflammatory diseases caused by telomere defects.

A full list of collaborating authors, research support and disclosures can be found with the full paper.

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