Summary: Mutations of the GBA gene, a known risk factor for Parkinson’s disease, appear to also influence the development of cognitive decline, a new study reports.
Source: Salk Institute.
Ever since researchers connected the shortening of telomeres–the protective structures on the ends of chromosomes–to aging and disease, the race has been on to understand the factors that govern telomere length. Now, scientists at the Salk Institute have found that a balance of elongation and trimming in stem cells results in telomeres that are, as Goldilocks would say, not too short and not too long, but just right.
The finding, which appears in the December 5, 2016, issue of Nature Structural & Molecular Biology, deepens our understanding of stem cell biology and could help advance stem cell-based therapies, especially related to aging and regenerative medicine.
“This work shows that the optimal length for telomeres is a carefully regulated range between two extremes,” says Jan Karlseder, a professor in Salk’s Molecular and Cell Biology Laboratory and senior author of the work. “It was known that very short telomeres cause harm to a cell. But what was totally unexpected was our finding that damage also occurs when telomeres are very long.”
Telomeres are repetitive stretches of DNA at the ends of each chromosome whose length can be increased by an enzyme called telomerase. Our cellular machinery results in a little bit of the telomere becoming lopped off each time cells replicate their DNA and divide. As telomeres shorten over time, the chromosomes themselves become vulnerable to damage. Eventually the cells die. The exception is stem cells, which use telomerase to rebuild their telomeres, allowing them to retain their ability to divide, and to develop (“differentiate”) into virtually any cell type for the specific tissue or organ, be it skin, heart, liver or muscle–a quality known as pluripotency. These qualities make stem cells promising tools for regenerative therapies to combat age-related cellular damage and disease.
“In our experiments, limiting telomere length compromised pluripotency, and even resulted in stem cell death,” says Teresa Rivera, a Salk research associate and first author of the paper. “So then we wanted to know if increasing telomere length increased pluripotent capacity. Surprisingly, we found that over-elongated telomeres are more fragile and accumulate DNA damage.”
Karlseder, Rivera and colleagues began by investigating telomere maintenance in laboratory-cultured lines of human embryonic stem cells (ESCs). Using molecular techniques, they varied telomerase activity. Perhaps not surprisingly, cells with too little telomerase had very short telomeres and eventually the cells died. Conversely, cells with augmented levels of telomerase had very long telomeres. But instead of these cells thriving, their telomeres developed instabilities.
“”We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to initiation of cancer,” says Karlseder, who also holds the Donald and Darlene Shiley Chair. “These experiments question the generally accepted notion that artificially increasing telomeres could lengthen life or improve the health of an organism.”
The team observed that very long telomeres activated trimming mechanisms controlled by a pair of proteins called XRCC3 and Nbs1. The lab’s experiments show that reduced expression of these proteins in ESCs prevented telomere trimming, confirming that XRCC3 and Nbs1 are indeed responsible for that task.
Next, the team looked at induced pluripotent stem cells (iPSCs), which are differentiated cells (e.g., skin cells) that are reprogrammed back to a stem cell-like state. iPSCs–because they can be genetically matched to donors and are easily obtainable–are common and crucial tools for potential stem cell therapies. The researchers discovered that iPSCs contain markers of telomere trimming, making their presence a useful gauge of how successfully a cell has been reprogrammed.
“Stem cell reprogramming is a major scientific breakthrough, but the methods are still being perfected. Understanding how telomere length is regulated is an important step toward realizing the promise of stem cell therapies and regenerative medicine,” says Rivera.
Other authors included Candy Haggblom of the Salk Institute and Sandro Cosconati of the Second University of Naples.
Funding: The work was funded by the California Institute for Regenerative Medicine training grant TG2-01158, the Salk Institute Cancer Center Core Grant (P30CA014195), the National Institutes of Health (R01GM087476, R01CA174942), the Highland Street Foundation, the Fritz B. Burns Foundation, the Emerald Foundation and the Glenn Center for Research on Aging.
Source: Salk Institute
Image Source: NeuroscienceNews.com image is credited to Salk Institute.
Original Research: Abstract for “A balance between elongation and trimming regulates telomere stability in stem cells” by Teresa Rivera, Candy Haggblom, Sandro Cosconati & Jan Karlseder in Nature Structural & Molecular Biology. Published online December 5 2016 doi:10.1038/nsmb.3335
A balance between elongation and trimming regulates telomere stability in stem cells
Telomere length maintenance ensures self-renewal of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs); however, the mechanisms governing telomere length homeostasis in these cell types are unclear. Here, we report that telomere length is determined by the balance between telomere elongation, which is mediated by telomerase, and telomere trimming, which is controlled by XRCC3 and Nbs1, homologous recombination proteins that generate single-stranded C-rich telomeric DNA and double-stranded telomeric circular DNA (T-circles), respectively. We found that reprogramming of differentiated cells induces T-circle and single-stranded C-rich telomeric DNA accumulation, indicating the activation of telomere trimming pathways that compensate telomerase-dependent telomere elongation in hiPSCs. Excessive telomere elongation compromises telomere stability and promotes the formation of partially single-stranded telomeric DNA circles (C-circles) in hESCs, suggesting heightened sensitivity of stem cells to replication stress at overly long telomeres. Thus, tight control of telomere length homeostasis is essential to maintain telomere stability in hESCs.
“A balance between elongation and trimming regulates telomere stability in stem cells” by Teresa Rivera, Candy Haggblom, Sandro Cosconati & Jan Karlseder in Nature Structural & Molecular Biology. Published online December 5 2016 doi:10.1038/nsmb.3335