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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.
Early Genome Catastrophes Can Cause Non-Smoking Lung Cancer
Some teenagers harbor catastrophic changes to their genomes that can lead to lung cancer later on in life, even if they never smoke (Professor Young Seok Ju at the Graduate School of Medical Science and Engineering) Catastrophic rearrangements in the genome occurring as early as childhood and adolescence can lead to the development of lung cancer in later years in non-smokers. This finding, published in Cell, helps explain how some non-smoking-related lung cancers develop. Researchers at KAIST, Seoul National University and their collaborators confirmed that gene fusions in non-smokers mostly occur early on, sometimes as early as childhood or adolescence, and on average about three decades before cancer is diagnosed. The study showed that these mutant lung cells, harboring oncogenic seeds, remain dormant for several decades until a number of further mutations accumulate sufficiently for progression into cancer. This is the first study to reveal the landscape of genome structural variations in lung adenocarcinoma. Lung cancer is the leading cause of cancer-related deaths worldwide, and lung adenocarcinoma is its most common type. Most lung adenocarcinomas are associated with chronic smoking, but about a fourth develop in non-smokers. Precisely what happens in non-smokers for this cancer to develop is not clearly understood. Researchers analyzed the genomes of 138 lung adenocarcinoma patients, including smokers and non-smokers, with whole-genome sequencing technologies. They explored DNA damage that induced neoplastic transformation. Lung adenocarcinomas that originated from chronic smoking, referred to as signature 4-high (S4-high) cancers in the study, showed several distinguishing features compared to smoking-unrelated cancers (S4-low). People in the S4-high group were largely older, men and had more frequent mutations in a cancer-related gene called KRAS. Cancer genomes in the S4-high group were hypermutated with simple mutational classes, such as the substitution, insertion, or deletion of a single base, the building block of DNA. But the story was very different in the S4-low group. Generally, mutational profiles in this group were much more silent than the S4-high group. However, all cancer-related gene fusions, which are abnormally activated from the merging of two originally separate genes, were exclusively observed in the S4-low group. The patterns of genomic structural changes underlying gene fusions suggest that about three in four cases of gene fusions emerged from a single cellular crisis causing massive genomic fragmentation and subsequent imprecise repair in normal lung epithelium. Most strikingly, these major genomic rearrangements, which led to the development of lung adenocarcinoma, are very likely to be acquired decades before cancer diagnosis. The researchers used genomic archaeology techniques to trace the timing of when the catastrophes took place. Researchers started this study seven years ago when they discovered the expression of the KIF5B-RET gene fusion in lung adenocarcinoma for the first time. Professor Young-Seok Ju, co-lead author from the Graduate School of Medical Science and Engineering at KAIST says, “It is remarkable that oncogenesis can begin by a massive shattering of chromosomes early in life. Our study immediately raises a new question: What induces the mutational catastrophe in our normal lung epithelium.” Professor Young Tae Kim, co-lead author from Seoul National University says, “We hope this work will help us get one step closer to precision medicine for lung cancer patients.” The research team plans to further focus on the molecular mechanisms that stimulate complex rearrangements in the body, through screening the genomic structures of fusion genes in other cancer types. This study was supported by the National Research Foundation of Korea (NRF), Korea Health Industry Development Institute (KHIDI), Suh Kyungbae Foundation, the College of Medicine Research Foundations at Seoul National University and others. Figure. (Smoking-unrelated oncogenesis of lung cancers by gene fusions) Publication. Jake June-Koo Lee, Seongyeol Park et al., Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma Cell 177, June 13 2019, online publication ahead of print at May 30, 2019 https://doi.org/10.1016/j.cell.2019.05.013 Profile: Prof Young Seok Ju, MD, PhD email@example.com http://julab.kaist.ac.kr Associate Professor Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST) Daejeon 34141, Korea Profile: Prof Young Tae Kim, MD, PhD firstname.lastname@example.org Professor Seoul National University Cancer Research Institute Department of Thoracic and Cardiovascular Surgery Seoul National University Hospital Seoul 03080, Korea
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