Two-point and one-line exploration of the "young factor" of cell life

Two-point and one-line exploration of the "young factor" of cell life

April 09, 2019 Source: Science and Technology Daily

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In the illusion of the source of life, people always go to the hidden places to look for "not old springs", in fact, the secret of life is not in its smallest unit -

On March 26th, Chinese scientists first identified the “young factor”, the poly-calorin 4 (CBX4), which rejuvenated aging mesenchymal stem cells, and verified its function. The relevant research results were published in the Cell Report. "on.

A few days later, on April 1st, "Public Science Library Biology" published another new discovery of the same team of scientists, for the first time established a "young pathway" in human mesenchymal stem cells - YAP-FOXD1, and proved Activation of this pathway reduces cellular aging and osteoarthritis.

If the former is a team of scientists who have discovered "the old springs" in stem cells, then the latter's research is "two points and one line" to determine the "water of youth" of cell life.

"This study reveals the role and molecular mechanism of the YAP-FOXD1 pathway in human stem cell de-aging and osteoarthritis gene therapy." Liu Guanghui, a researcher at the Institute of Biophysics, Chinese Academy of Sciences, introduced the study by the Institute of Biophysics, Chinese Academy of Sciences. The research team of Liu Guanghui was completed in cooperation with the Tang Fuyue Research Group of Peking University and the Qujing Research Group of the Institute of Zoology of the Chinese Academy of Sciences. After five years of efforts, the research team proved the existence of the YAP-FOXD1 pathway through the intertwined cellular gene regulatory network. Experiments at the cellular and animal levels have demonstrated its function.

For the oncogene "recognition" YAP protein acts as a "young factor"

The first APAP in the YAP-FOXD1 pathway is the YAP protein. Searching for the "CV" of YAP protein on the Internet, we can find that the most closely related to it is a Hippo signal pathway called "Hippo Channel" in the industry.

Once the upstream of the "Hiparian pathway" receives a signal to inhibit growth, after a series of kinase phosphorylation reactions, it finally acts on the downstream effector YAP protein in the form of phosphorylation, which determines the phosphorylation of YAP protein.

If not phosphorylated, without the drag of the phosphorylated group "tail", YAP can easily enter the nucleus and enter the gene-regulated base camp. At this time, YAP plays the role of “transporter”. Its emergence in the base camp attracts the gene's activity. It chooses to combine with its target gene and “passes the order”, urging the target gene to express the corresponding RNA and protein. Affect the life activities of cells.

"We first found YAP, a well-defined transcriptional co-activator." Liu Guanghui said that in the nucleus, YAP can bind to its transcription factor "partner" TEAD to activate transcription of downstream target genes.

If YAP carries the "tail" of the phosphorylation group, it will be blocked in the cytoplasm, and YAP will not be able to "transfer" into the nucleus, the transcriptional expression of the downstream gene will be inhibited, and cell proliferation will be inhibited.

It has been reported that if YAP is frequently "transmitted" and unrestrained, it will allow cells to proliferate without restriction, which may lead to tumors, and is therefore considered to be an "oncogene."

The characteristics of YAP give the research team two tasks: First, it is functionally proved whether its existence is related to the "young state" of the cell; second, how does it pass the "command" and regulate the function of the functional gene? ? Who is its "receiver" and has it been found by other scientists before?

To answer the first question, the team verifies from both positive and negative perspectives. "We have discovered a series of proteins that can delay the aging of human mesenchymal stem cells through CRISPR/Cas9-mediated gene editing technology. After these proteins are knocked out, cells will have a phenotype that accelerates aging." The first author of the paper, Chinese Academy of Sciences Fu Lina, a Ph.D. student at the Institute of Biophysics, said that the work of gene knockout began with human embryonic stem cells. By introducing three different plasmids, the research team made the deletion of the gene responsible for encoding the YAP protein in the stem cell genome.

"Knockout genomic DNA is probably a few thousand bases, although knocking out a few bases may cause the YAP factor to lose its function, but it is likely to lead to the production of new abnormal proteins, leading to factors that cannot be ruled out." Na said. The team must ensure complete silence of the YAP gene. To this end, they have improved the CRISPR/Cas9 gene editing technology to enable the deletion of large fragments of the large YAP locus.

Using the CRISPR/Cas9 gene editing technology, the team obtained YAP-specific knockout human embryonic stem cells, and induced differentiation of human embryonic stem cells into mesenchymal stem cells by directed differentiation. "YAP-deficient human mesenchymal stem cells exhibit a severe accelerated aging phenotype." Liu Guanghui said that YAP plays a key role in maintaining young adult stem cells, although YAP has been shown to have "oncogenes" in certain tumor cells. The function, but in the human mesenchymal cells, it plays the role of "young factor."

The new "two points and one line" find YAP protein "hardcore partner" and "receiver"

YAP initiates transcription of downstream genes through interaction with the transcription factor TEAD, which means that TEAD and YAP are "hardcore partners." Previous studies have found that YAP and TEAD form a protein complex through the interaction between the N-terminus of YAP and the C-terminus of TEAD, which plays a key role in YAP-mediated cell proliferation.

The team's second task is to find the "receiver" of YAP. "We hypothesized that one or some of the target genes of YAP mediate the regulation of younger human mesenchymal stem cells." Liu Guanghui said, "Through series of experiments, we found that YAP can transcriptionally activate FOXD1, a novel YAP target gene. Never before reported."

The forkhead (FOX) protein family contains more than 50 transcription factors that play a role in many biological processes such as embryonic development, cell cycle regulation, carbohydrate and lipid metabolism, and senescence regulation. FOXD1 is one of the transcription factors. Fu Lina explained that it has been previously reported that FOXD1 regulates organ development and has activity to promote cell proliferation and cell reprogramming.

"We first performed RNA sequencing on YAP knockout human mesenchymal stem cells, and further combined with the prediction of transcription factor binding elements, we concluded that FOXD1 may be a novel target gene for YAP." Fu Lina said, subsequently, in order to verify the inference, The team used the chromatin immunoprecipitation (ChIP) method to "fish" the protein that specifically binds to the FOXD1 promoter DNA (ie, YAP), which ultimately proved that FOXD1 took the "command" from the YAP and opened the regulatory cell "young". Molecular program.

"YAP is upstream and FOXD1 is downstream. They are a community of fate." Liu Guanghui explained that the expression of YAP and FOXD1 was consistently down-regulated with cell senescence.

Or assist gene therapy in the future to effectively intervene in aging-related diseases

Starting from stem cells, discovering the mechanism and mechanism, and then returning to the cell and living body to verify, the discovery of "the river of youth" must prove its "magic power" in the organism.

"We demonstrated the de-aging effect of the YAP-FOXD1 pathway in three cell aging models, and overexpression of YAP or FOXD1 allowed senescent human mesenchymal stem cells to regain proliferative capacity," Fu Lina said. On the other hand, the results of cell experiments suggest that overexpression of YAP or FOXD1 may make aging animal mesenchymal tissues (such as joints) younger.

The team then implemented gene therapy on the animals. "We demonstrated the feasibility and efficacy of overexpression of YAP or FOXD1 protein as a gene therapy protocol for osteoarthritis in mice." Liu Guanghui said that the team uses a lentiviral vector as a gene introduction vector to encode YAP or FOXD1 protein. Lentivirus was injected into the joint cavity of mice with osteoarthritis. Several weeks of YAP or FOXD1 gene therapy can significantly reduce the proportion of senescent cells in articular cartilage, effectively inhibit articular cartilage degradation and joint cavity inflammation, and improve the pathological phenotype of osteoarthritis in many ways.

Osteoarthritis is a typical human disease that is closely related to cellular aging. These findings all prove that the introduction of stem cells "young factor" by genes is expected to treat aging-related diseases represented by osteoarthritis in the future. Finding a "no old spring" or "healthy river" will provide a clear target for gene therapy, and ultimately provide an effective solution to the intervention of aging-related diseases, and clinical application. (Reporter Zhang Jiaxing)

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