New study identifies chromosome ends as potential target for preventing degenerative diseases

We rely on our cells to be able to divide and reproduce, whether to replace sun-damaged skin or to replenish our blood supply and recover from injury. Chromosomes carry all of our genetic instructions and must be replicated in complete form during cell division. Telomeres cover the ends of chromosomes and play a key role in the cell renewal process, which has a direct impact on health and disease.

Telomerase plays a key role in maintaining telomere length when chromosomes are replicated during cell division. Carol Greider, a professor at the University of California, Santa Cruz, has been researching telomeres and telomerase for more than 30 years. The impact of the discoveries she made during that time was why she, along with two colleagues, received the 2009 Nobel Prize in Physiology or Medicine.

So Grede’s latest findings on telomeres shouldn’t surprise her. However, they did it.

Published online today at science,A new research Telomere length was found to follow a different pattern than hitherto understood. This study found that different chromosomes have different end-specific telomere length distributions, rather than all chromosomes having telomere lengths that fall within a general range from shortest to longest.

Greder said the discovery means we don’t yet fully understand the molecular processes that regulate telomere length. This is important because telomere length affects human health: “When telomeres are too short, you develop age-related degenerative diseases such as pulmonary fibrosis, bone marrow failure, and immune suppression,” Greder said. “On the other hand, if telomeres are too long, it can make you susceptible to certain types of cancer.”

The paper’s lead author, Kayarash Karimian, is a former Ph.D. student. student in Greder’s lab at the Johns Hopkins University School of Medicine. Other co-authors of the study include researchers at Dana-Farber Cancer Institute, Harvard Medical School and the University of Pittsburgh.Greider Distinguished Professor Molecular, Cellular and Developmental Biology A professor at UC Santa Cruz and a professor at Johns Hopkins University, is the paper’s senior author and led the work.

Why length matters

Without telomerase, telomeres would get shorter and shorter as cells divide again and again. Over the past 30 years, studies by Greder et al. have confirmed that short telomeres can lead to degenerative diseases and have shown that telomere lengths fall within a certain range.

But this paper challenges the scientific consensus, showing that the range of single telomere lengths is too broad. In the study, researchers measured the telomeres of 147 people and found that the average telomere length across all chromosomes in one person was 4,300 DNA bases. Then, when they isolated specific chromosomes, they found that most telomere lengths differed significantly from this average. In one case, the length differed by as much as 6,000 bases, which Greider described as “jaw-dropping.”

Additionally, they found that across all 147 individuals, the same telomeres were often either the shortest or the longest, meaning that telomeres at the ends of specific chromosomes may be the first to trigger stem cell failure.

Innovation in Nanopore Sequencing

To make such precise measurements at the molecular level, Greder’s team used a technique Invented at UC Santa Cruz A revolutionary DNA and RNA reading method known as “nanopore sequencing” has had a huge impact on genomics research since it was first launched as a commercial product MinION in 2014.

Nanopore technology has enabled some of the most significant advances in genomics, such as Gapless human genomeand COVID-19 genome sequencing—critical to the fight to end the pandemic. UC Santa Cruz licensed the concept of nanopore sequencing technology to British company Oxford Nanopore Technologies, which made the MinION, the first handheld DNA sequencer.

Notably, for the inventor of nanopore sequencing, Greder’s research demonstrates the technology’s emerging ability to advance scientific research. Mark Akeson, professor emeritus of biomolecular engineering at the University of California, Santa Cruz, noted that two preprint studies confirming the basic findings of Greder’s paper have also been posted online.

“In my opinion, this is the most important nanopore paper focusing on human biology since the launch of MinION,” Akeson said. “It is easy to imagine widespread clinical applications of their telomere length determination.”

Akerson and David Deamer, also a professor emeritus of biomolecular engineering in the Baskin School of Engineering, were honored last year at the Library of Congress for their invention of nanopore sequencing. Their colleague and friend Daniel Branton, a Harvard biologist and co-inventor of the technology, was also honored.

Impact on disease prevention

Such precise DNA readings allowed Greider’s team to pinpoint sequences near telomeres and hypothesize that these regions are where telomerase regulates length. If this is true, Greder said, these regions and the proteins that bind there could serve as potential targets for new drugs to prevent disease.

In addition, their process of “telomere analysis” through nanopore sequencing can serve as a model for the development of other MinION-based high-throughput drug screening assays.

“This easy-to-use technology has broad potential for applications in research, diagnostics and drug development,” Greder said. “This work demonstrates that mechanisms of telomere length regulation have not yet been discovered; exploring these mechanisms will provide new opportunities for treating cancer and certain diseases.” Provide new methods for treating degenerative diseases.

The study, “Human telomere length is chromosome end-specific and conserved among individuals,” was funded by the National Institutes of Health (R35CA209974 awarded to Greider and R01HL166265), Bloomberg Distinguished Professor at Johns Hopkins University and National Science Foundation Graduate Research Grant Fellowship Program.