This gene allows cells to “reborn with memories”!

If you were asked to be reborn in childhood with your current memories, would you choose to remember the answers to the college entrance examination or the winning numbers of a certain lottery? This " rebirth with memories " plot has become the theme of many online novels. Although for the whole person this is just a fantasy, for a single cell, this fantasy has become a reality!

On October 12, 2023, the research groups of Liu Guanghui and Qu Jing from the Institute of Zoology, Chinese Academy of Sciences, together with the research groups of Zhang Weiqi and Ren Jie from the Beijing Institute of Genomics, Chinese Academy of Sciences, published an online research paper titled Genome-wide CRISPR activation screening in senescent cells reveals SOX5 as a driver and therapeutic target of rejuvenation in Cell Stem Cell. In the paper, the authors reported that the newly discovered SOX5 gene can allow cells to undergo cell rejuvenation without changing their identity (carrying their own "memory"), thus rejuvenating aging cells.

This discovery provides new research ideas for studying the cellular aging process and treating aging-related diseases. So, how was this gene discovered? What is its significance for cell regeneration?

Figure 1 Screenshot of the article title (Image source: cell)

The tortuous exploration of anti-aging

The human body is made up of cells, and human aging is closely related to the aging of human cells. As cells perform their life activities, their proliferation and differentiation abilities and physiological functions gradually decline over time, and the genes, proteins, and organelles in the cells also undergo significant changes. Cells are no longer as energetic as they were when they were young, and their reactions slow down, leading to the degradation of overall physiological functions.

Cell aging is closely related to the aging of the body and diseases. In-depth research on the phenomenon of cell aging is conducive to the prevention and treatment of related diseases. Therefore, scientists have long begun to study the molecular biology of cell aging and try to develop methods to reverse aging. Simply put, it is to allow cells to "rejuvenate" and regain vitality.

Previously, Liu Guanghui, a researcher at the Institute of Zoology, Chinese Academy of Sciences, and his collaborators used the latest somatic cell reprogramming technology to successfully reverse the aging fibroblasts in children with progeria.

Progeria is a rare genetic disease in which patients show a series of aging symptoms such as wrinkles, hair loss, arteriosclerosis, and physical weakness in infancy, and usually die of various aging diseases before the age of 13. The cause of this disease is the premature and irreversible aging of cells throughout the body caused by gene mutations.

Figure 2 A child with progeria (left), a normal human cell nucleus (upper right), and a child's cell nucleus (lower right) (Image source: Reference 2)

Researcher Liu Guanghui's team successfully made the patient's fibroblasts "turn back time" by injecting the " Yamananaka Four Factors " into the cells. These are four transcription factors discovered by 2012 Nobel Prize winner Shinya Yamanaka - Oct4, Sox2, Klf4, c-Myc (collectively known as OSKM), which can reverse the cell clock.

Although the final result is that the aging of diseased cells is reversed, the "Yamananaka Four Factors" also bring many risks while curing diseases. The biggest problem is that while the Yamanaka Four Factors "rejuvenate" cells, they also erase the differentiation state of the cells and change the cell identity. Although the reprogrammed cells are reborn, they also lose their memory.

In other words, although the cells have "rejuvenated", they have completely become ignorant children, not knowing what their physiological functions are. Although they have become young again, they have forgotten their responsibilities.

Figure 3 The role of Yamanaka factors in somatic cell reprogramming

(Image source: Reference 3)

Another problem is that many scientists around the world have tried to use Yamanaka factors to fight aging on animals, but many of the experimental animals later died of tumors or cancer. It seems that there are still many problems to be solved if we want to use this method to fight aging.
After re-evaluating the experiment, Liu Guanghui's team believed that there might be some problems with the Yamanaka factor, so they embarked on the road of searching for new "aging reversal genes."

The new genes to be looked for this time need to have the following characteristics: first, they can make cells rejuvenated; second, they can not erase the memory of cells while making them rejuvenated, but they must remember their own functions; finally, they must ensure safety as much as possible and not create too much risk.

Starting from the beginning, searching for the "rebirth" gene

Since we are going to do it, we should do it thoroughly. Researcher Liu Guanghui's team used the self-built human mesenchymal precursor cell system as the material to check more than 20,000 genes in the cells one by one to see which genes can play a role in delaying aging.

This screening process uses a tool called " CRISPR activation ". CRISPR is a common gene editing tool. After modification, this tool can remove activation factors for specific genes, thereby enhancing their functions. Researcher Liu Guanghui's team sent enhancement instructions to more than 20,000 genes in cells one by one to observe which genes can be enhanced to play a role in cell regeneration.

After a painstaking investigation, the team successfully identified a series of genes that, when activated, can fully exert the effect of delaying the aging of human mesenchymal precursor cells. Therefore, this series of genes are our potential secret weapons against cell aging.

Among these genes, one gene has received the most attention from scientists, and that is the SOX5 gene . As the name suggests, SOX5 and SOX2 in the Yamanaka factor are genes in the same gene family, and the activation of SOX5 has shown a strong ability to promote cell rejuvenation. Therefore, scientists conducted a series of follow-up verifications around SOX5.

The “Triple Door” to Verify Anti-Aging Function

To prove that a gene has anti-aging functions, we need clues in three aspects: at the molecular level, we need to find evidence of gene interaction, that is, which genes this gene will interact with; at the cellular level , we need to see the reversal of cell aging by this gene; at the level of individual organisms , we need to prove that this gene can really rejuvenate aged biological organs.

On these levels, the SOX5 gene did not disappoint us.

First, at the molecular level, after using a variety of screening technologies, scientists found the "connector" of SOX5 - the HMGB2 gene , which was proven to be an aging-suppressing gene in previous studies. SOX5 can activate the expression of HMGB2, thereby starting the cell regeneration process. The study also found that if the SOX5 gene in the cell is inhibited, the expression of HMGB2 will also be inhibited, and the cell will accelerate aging. Therefore, the molecular mechanism of SOX5's function has been confirmed.

Figure 4 SOX5 gene is a long-range enhancer of other genes

(Image source: Reference 1)

Secondly, how does SOX5 perform at the cellular level? Experiments have found that SOX5 can indeed rejuvenate many types of aging human cells. What is valuable is that this rejuvenation is not simply "turning back the clock", but rejuvenating without changing the identity of the cells , which is equivalent to regenerating these cells while maintaining their memory.

The most amazing thing is that the SOX5 gene can really play a role in "rejuvenation" in mice! In order to study the function of the SOX5 gene in individual aging, the research team selected a group of elderly mice and performed SOX5 gene therapy in their knee joints. The knee joints of elderly mice often have aging phenomena such as osteophytes and synovial hyperplasia, inflammation, and cartilage wear. In the knee joints of mice treated with SOX5, osteophytes and synovial regeneration were significantly inhibited, and the cartilage regeneration ability was also enhanced. Most importantly, after treatment, the limb grip of elderly mice was significantly improved. It seems that the SOX5 gene really makes the legs and feet of these "grandfather mice" young again.

Figure 5 Using SOX5 gene to treat joints in aged mice

The rejuvenation effect is obvious (Image source: Reference 1)

Of course, the Yamanaka four factors can also do the job of treating joints in elderly mice, but SOX5 has two advantages that the Yamanaka four factors cannot match: first, SOX5 will not cause the erasure of cell differentiation traces, that is, it will not change the identity of the cells, and the cells can still maintain their original "memory"; in addition, compared with the four genes of Yamanaka, SOX5 works alone, has a shorter DNA length, may cause fewer side effects, and is safer during treatment.

In general, this study has found a series of new cell regeneration factors for us. The study of these genes will bring new possibilities for us to fight against aging and further deepen our theoretical understanding of the cell aging process. The special gene SOX5 may become a potential target for intervention in aging-related degenerative diseases due to its excellent characteristics.

References:

[1] Yaobin Jing, Xiaoyu Jiang, Qianzhao Ji, Zeming Wu, Wei Wang, Zunpeng Liu, Pedro Guillen-Garcia, Concepcion Rodriguez Esteban, Pradeep Reddy, Steve Horvath, Jingyi Li, Lingling Geng, Qinchao Hu, Si Wang, Juan Carlos Izpisua Belmonte, Jie Ren, Weiqi Zhang, Jing Qu, Guang-Hui Liu, Genome-wide CRISPR activation screening in senescent cells reveals SOX5 as a driver and therapeutic target of rejuvenation,Cell Stem Cell,Volume 30, Issue 11,2023,Pages 1452-1471.e10,ISSN 1934-5909,https://doi.org/10.1016/j.stem.2023.09.007.

[2] Scaffidi P, Gordon L, Misteli T (2005) The Cell Nucleus and Aging: Tantalizing Clues and Hopeful Promises. PLoS Biol 3(11): e395. https://doi.org/10.1371/journal.pbio.0030395

[3] Chiavellini P, Canatelli-Mallat M, Lehmann M, Gallardo MD, Herenu CB, Cordeiro JL, Clement J, Goya RG. Aging and rejuvenation - a modular epigenome model. Aging (Albany NY). 2021 Feb 24; 13:4734-4746. https://doi.org/10.18632/aging.202712

Author: Mu Xin

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