NT-1
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'Jumping Genes' Found to Alter Human Colon Genomes, Offering Insights into Aging and Tumorigenesis
The Korea Advanced Institute of Science and Technology (KAIST) and their collaborators have conducted a groundbreaking study targeting 'jumping genes' in the entire genomes of the human large intestine. Published in Nature on May 18 2023, the research unveils the surprising activity of 'Long interspersed nuclear element-1 (L1),' a type of jumping gene previously thought to be mostly dormant in human genomes. The study shows that L1 genes can become activated and disrupt genomic functions throughout an individual's lifetime, particularly in the colorectal epithelium.
(Paper Title: Widespread somatic L1 retrotransposition in normal colorectal epithelium, https://www.nature.com/articles/s41586-023-06046-z)
With approximately 500,000 L1 jumping genes, accounting for 17% of the human genome, they have long been recognized for their contribution to the evolution of the human species by introducing 'disruptive innovation' to genome sequences. Until now, it was believed that most L1 elements had lost their ability to jump in normal tissues of modern humans. However, this study reveals that some L1 jumping genes can be widely activated in normal cells, leading to the accumulation of genomic mutations over an individual's lifetime. The rate of L1 jumping and resulting genomic changes vary among different cell types, with a notable concentration observed in aged colon epithelial cells. The study illustrates that every colonic epithelial cell experiences an L1 jumping event by the age of 40 on average.
The research, led by co-first authors Chang Hyun Nam (a graduate student at KAIST) and Dr. Jeonghwan Youk (former graduate student at KAIST and assistant clinical professor at Seoul National University Hospital), involved the analysis of whole-genome sequences from 899 single cells obtained from skin (fibroblasts), blood, and colon epithelial tissues collected from 28 individuals. The study uncovers the activation of L1 jumping genes in normal cells, resulting in the gradual accumulation of genomic mutations over time. Additionally, the team explored epigenomic (DNA methylation) sequences to understand the mechanism behind L1 jumping gene activation. They found that cells with activated L1 jumping genes exhibit epigenetic instability, suggesting the critical role of epigenetic changes in regulating L1 jumping gene activity. Most of these epigenomic instabilities were found to arise during the early stages of embryogenesis. The study provides valuable insights into the aging process and the development of diseases in human colorectal tissues.
"This study illustrates that genomic damage in normal cells is acquired not only through exposure to carcinogens but also through the activity of endogenous components whose impact was previously unclear. Genomes of apparently healthy aged cells, particularly in the colorectal epithelium, become mosaic due to the activity of L1 jumping genes," said Prof. Young Seok Ju at KAIST.
"We emphasize the essential and ongoing collaboration among researchers in clinical medicine and basic medical sciences," said Prof. Min Jung Kim of the Department of Surgery at Seoul National University Hospital. "This case highlights the critical role of systematically collected human tissues from clinical settings in unraveling the complex process of disease development in humans."
"I am delighted that the research team's advancements in single-cell genome technology have come to fruition. We will persistently strive to lead in single-cell genome technology," said Prof. Hyun Woo Kwon of the Department of Nuclear Medicine at Korea University School of Medicine.
The research team received support from the Research Leader Program and the Young Researcher Program of the National Research Foundation of Korea, a grant from the MD-PhD/Medical Scientist Training Program through the Korea Health Industry Development Institute, and the Suh Kyungbae Foundation.
< Figure 1. Experimental design of the study >
< Figure 2. Schematic diagram illustrating factors influencing the soL1R landscape. >
Genetic composition of rc-L1s is inherited from the parents. The methylation landscape of rc-L1 promoters is predominantly determined by global DNA demethylation, followed by remethylation processes in the developmental stages. Then, when an rc-L1 is promoter demethylated in a specific cell lineage, the source expresses L1 transcripts thus making possible the induction of soL1Rs.
2023.05.22 View 4508 -
KAIST Offers Hope to Musicians with Dystonia
< Photo 1. Conductor and Pianist João Carlos Martins before the Recital at the Carnegie Hall preparing with his bionic gloves >
KAIST’s neuroscientist and professor, Dr. Daesoo Kim attended the “Conference for Musicians with Dystonia” supported by the World Health Organization (WHO) and the Carnegie Hall concert of legendary pianist João Carlos Martins, who is also a dystonia patient, to announce his team’s recent advancements toward finding a cure for dystonia.
On November 19, 2022, a “miracle concert” was held in Carnegie Hall. João Carlos Martins was a renowned world-class pianist in the 70s and 80s, but he had to put an end to his musical career due to focal dystonia in his fingers. But in 2020, he began using a bionic glove developed by industrial designer Ubiratã Bizarro Costa and after years of hard work he was back in Carnegie Hall as an 82-year-old man.
During the concert, he conducted the NOVUS NY orchestra in a performance of Bach, and later even played the piano himself. In particular, between his performances, he gave shout-outs to scientists studying dystonia including KAIST Professor Daesoo Kim, asking them to continue working towards curing rare diseases for musicians.
< Photo 2. Professor Daesoo Kim with Conductor and Pianist João Carlos Martins >
Musician’s dystonia affects 1-3% of musicians around the world and musicians make up approximately 5% of the total number of dystonia patients. Musicians who are no longer able to practice music due to the disease often experience stress and depression, which may even lead to suicide in extreme cases. Musicians are known to be particularly prone to such diseases due to excessive practice regimens, perfectionism, and even genetics. Currently, botulinum toxin (Botox) is used to suppress abnormal muscles, but muscle function suppression ultimately means that the musician is no longer able to play the instrument. João Carlos Martins himself underwent several Botox procedures and three brain surgeries, but saw no therapeutic results. This is why a new treatment was necessary.
Professor Daesoo Kim’s research team at KAIST took note of the fact that abnormal muscle tension is caused by excessive stress, and developed NT-1, a treatment that blocks the development of the symptoms of dystonia from the brain, allowing patients to use their muscles as they normally would. The research team published their findings in Science Advances in 2021, and João Carlos Martins invited Professor Daesoo Kim to the UN conference and his concert after reading this paper.
< Photo 3. Professor Daesoo Kim (3rd from the left) photographed with other guests at the recital including Dr. Dévora Kestel, the Director of the Mental Health and Substance Use at WHO, sharing the center with Conductor and Pianist João Carlos Martins >
During the UN conference held the day prior to the Carnegie Hall concert, Dr. Dévora Kestel, Director of the Mental Health and Substance Use at WHO, said, “Although dystonia is not as well-known, it is a common disease around the world, and needs our society’s attention and the devotion of many researchers.” Professor Daesoo Kim said, “NT-1 is a drug that blocks the cause of dystonia in the brain, and will allow musicians to continue practicing music. We aim to attain clinical approval in Korea by 2024.”
NT-1 is currently under development by NeuroTobe, a faculty-led start-up company at KAIST, headed by Professor Daesoo Kim as the CEO. The synthesis of the drug for clinical testing has been successfully completed, and it has shown excellent efficacy and safety through various rounds of animal testing. Unlike Botox, which takes a few days to show its therapeutic effects after receiving the procedure from a hospital, NT-1 shows its therapeutic effects within an hour after taking it. As a so-called “edible Botox”, it is expected to help treat various muscular diseases and ailments.
2022.12.27 View 8300