Will staying up late affect the next generation?

Why don't nerve cells turn into red blood cells?

Our lives originate from a fertilized egg, which gradually forms an individual composed of about 200 different types of cells, including nerve cells, muscle cells, blood cells, etc. The process from the fertilized egg to the formation of different types of cells is called cell differentiation.

In 1942, Waddington first proposed the concept of "epigenetic landscape" for the process of cell differentiation. The concept points out that the process of cell differentiation is similar to the process of a small ball sliding down from the top of the mountain to the bottom of the mountain. The small ball at the top of the mountain can choose a variety of paths to slide down. Different paths correspond to the differentiation process of different types of cells. In addition, Waddington believes that the process of cell differentiation is a one-way irreversible process. Once the ball reaches the bottom of the mountain, it cannot go anywhere else, for example, a nerve cell will not become a red blood cell.

However, the internal mechanism of the "epigenetic landscape" was not clear at the time. In this regard, scientists proposed two hypotheses: one is that as cells differentiate, some genes may be permanently lost in the cells; the other hypothesis is that the DNA in the cells is not lost, but the expression of some genes is turned off, resulting in the inability of these genetic information to be decoded into proteins and exert biological functions.

In 1958, John Gordon completed the famous clawed frog nuclear transplantation experiment, proving the second hypothesis. He transplanted the nucleus of the clawed frog's small intestinal epithelial cell into an egg cell with the nucleus removed, and the cell eventually successfully developed into a complete clawed frog individual. This experimental phenomenon proved that the nucleus of the differentiated cell has complete genetic information and can develop into a complete individual. At the same time, he proposed that the process of cell differentiation is not the loss of genes in the cell, but the expression of some unnecessary genes in the cell is turned off.

On the basis of keeping the DNA information unchanged, the function or characteristics of the cell can be changed by changing the state of genetic information decoding. This is the underlying principle of what we now call "epigenetics".

How is epigenetic inheritance achieved? Modification, modification, and modification

At the material level, epigenetics can be simply understood as additional chemical modifications on or around DNA. So, which epigenetic-related chemical modifications can affect the decoding state of genes in cells?

Human cells contain 46 chromosomes (23 pairs). Chromosomes are mainly composed of DNA and proteins called histones. DNA is first wrapped around an octamer consisting of eight histones to form a nucleosome structure. Many nucleosomes are connected in series to form a linear structure, which is then folded and compressed in various ways to form chromosomes.

If the linear nucleosome structure is likened to wool, the chromosome is a sweater. In fact, on each chromosome sweater, in addition to wool, there are also various decorations - different types of chemical modifications. Some of these chemical modifications are inherited, and some are gradually formed under the influence of the acquired environment. These chemical modifications are like traffic lights for gene expression, telling cells which genes need to be expressed and which genes do not need to be expressed.

The methylation modification on DNA, the methyl group is inserted into the base of DNA like a label, which tells the "transcription machinery" not to get close, preventing the genes on the DNA from being decoded into proteins. There are also various chemical modifications on the histones of nucleosomes, including acetylation, methylation, phosphorylation, etc. If there are a large number of methylation modifications on the histones, it will make the chromosomes appear dense, like a ball of yarn, making it impossible for the "transcription machinery" to get close to the genes located therein, and these genes will not be expressed. But if there are a large number of acetylation modifications on the histones. Then the corresponding chromosomes will appear loose, and the "transcription machinery" can easily get close to the genes located therein, causing the proteins to be expressed.

Let’s look at the example of DNA methylation regulating gene expression: X chromosome inactivation and calico cats

The sex of mammals is determined by the sex chromosomes X and Y. Males have one X and one Y chromosome, while females have two X chromosomes.

There are thousands of genes distributed on the X chromosome. If the genes on both X chromosomes in female cells are expressed, then compared with male cells, female cells will contain twice the dosage of X chromosome gene encoded proteins. Such consequences are catastrophic for cells. In fact, the expression of X chromosome gene-related proteins in female cells is comparable to that in male cells. What mechanism does the cell use to achieve this dosage compensation process of X chromosome gene expression?

Scientific research shows that in female cells, one of the two X chromosomes is inactivated, causing the genes on the inactivated X chromosome to be silenced and unable to express proteins. This X chromosome inactivation is mediated by DNA methylation.

The calico cats we see in daily life have black, white and yellow fur, and calico cats are often female. This fur color phenomenon is closely related to X chromosome inactivation.

The specific internal reason is that the gene controlling yellow and black fur color is located on the cat's X chromosome; and the cat's belly fur color is generally white, which is regulated by the albino gene, which is located on the autosome. Since male cats have only one X chromosome, they either carry the gene encoding yellow fur color or the gene encoding black fur color, so male cats mainly show yellow and white or black and white fur color. Female cats carry two X chromosomes. Under the action of DNA methylation, one of the two X chromosomes will be randomly inactivated, and most of the genes on the inactivated X chromosome cannot compile proteins.

If one of the two X chromosomes of a female cat carries a gene for yellow fur color and the other carries a gene for black fur color, under the influence of random inactivation of X chromosomes, some cells inactivate the X chromosome where the yellow fur color gene is located, and some cells inactivate the X chromosome where the black fur color gene is located. In addition, the effect of the albino gene on the autosome eventually causes the female cat to show a state where yellow, black, and white fur colors coexist. Therefore, DNA methylation mainly affects the characteristics of cells by preventing gene expression in cells.

We look very similar to our parents because our parents passed on their genes to us. So will our parents' epigenetic information be passed on to us? The answer is yes.

The medium for the transmission of genetic information is the germ cell. Our individuals develop from the fertilized egg obtained after the fertilization of sperm and egg cells. Parents pass genetic information to their offspring through sperm cells and egg cells respectively. After fertilization, although the epigenetic modifications on the chromosomes from the parents will undergo drastic erasure or re-establishment to achieve normal development of the embryo, some epigenetic information will be inherited and maintained from the parents.

A classic example is gene imprinting. We humans are diploid organisms, and we have two copies of each gene, one from the father and one from the mother. In a class of genes called imprinted genes, some genes are expressed by genes from the father and genes from the mother are silenced, while other genes are expressed by genes from the mother and genes from the father are silenced. This phenomenon is called gene imprinting. Gene imprinting has been shown to be related to DNA methylation. The DNA that regulates the expression of imprinted genes is methylated in one parent, and the gene from that parent is silenced. In the fertilized egg, the DNA methylation information related to gene imprinting from the parents will be inherited and maintained. In addition, in zebrafish, the offspring embryonic individuals will completely inherit the DNA methylation pattern from the father.

Now we can answer these questions.

As our understanding of epigenetic mechanisms deepens, answers to many questions are becoming clearer, such as differences between twins, the genetic nature of aging, and the impact of the environment on genes.

Identical twins have the same DNA information, but there are many differences between them. Researchers found that the levels of various chemical modifications on chromosomes between identical twins were very similar when they were 3 years old, but the differences increased significantly when they were 50 years old. This result also shows that even if the genes are the same or similar, the acquired living environment or living habits will greatly change the epigenetic state in the cells, affect the pattern of gene expression, and thus affect the health of the body.

During the aging process, the epigenetic state will also change significantly. Compared with young cells, the expression of histones, DNA methylation, histone modification levels, especially the inhibitory histone modification levels in old cells are significantly reduced, while the levels of some activating histone modifications are significantly increased, resulting in disordered gene expression in old cells and some abnormal gene activation.

Male mice that have been on a high-fat diet for a long time will show symptoms such as weight gain and obesity, accompanied by diabetes-related manifestations such as glucose intolerance and insulin resistance. The epigenetic state of their sperm cells has also changed, specifically manifested in a significant decrease in the overall level of DNA methylation in sperm cells, and abnormal DNA methylation of some genes related to embryonic development. If male mice on a high-fat diet are mated with female mice on a normal diet, although the offspring born do not show symptoms of obesity, they show abnormal insulin secretion and glucose intolerance in glucose tolerance tests.

Why do the female offspring of male mice fed a high-fat diet show glucose intolerance? One possible internal mechanism is that the DNA methylation of the Il13ra2 gene in the pancreatic islets of female offspring decreases, leading to a significant increase in the expression of the Il13ra2 gene, which ultimately leads to abnormal β cells in the pancreatic islets. This shows that daily eating habits not only change our own epigenetic state, but also can affect the health of our offspring through epigenetics.

In addition, will serious sleep problems affect our epigenetics? Modern technology has brought a lot of convenience to our lives. However, due to work pressure, mental stress, and some bad living habits such as watching mobile phones and playing games before going to bed, more than 300 million people in my country have sleep disorders. Research on mice and humans provides us with some clues.

In sleep-deprived mice, the expression levels of DNA methyltransferases Dnmt3a1 and Dnmt3a2, which are involved in the establishment of DNA methylation, increased significantly, suggesting that sleep deprivation can cause an increase in DNA methylation. A study of twins revealed that twins with different work and rest habits showed different DNA methylation patterns. In twins, the DNA methylation levels of about 50 genes changed in individuals with shorter sleep time compared to those with longer sleep time. After a night without sleep, some circadian rhythm-related genes and metabolism-related genes will have increased DNA methylation levels. Sleep disorders not only affect DNA methylation, but also lead to abnormal histone modifications, including histone acetylation.

In general, epigenetics can regulate the biological characteristics of cells and individuals by regulating the expression state of genes without changing the DNA sequence information. It is affected by our living environment, work and rest, diet and other habits, even our parents’ living environment, changing the epigenetic state of human cells, affecting the normal expression of genes, and is directly related to our physical health.

Finally, let’s answer a few questions about epigenetics.

Q1

Lamarck said, "The giraffe's neck became longer because it needed to frequently stretch its neck to eat leaves from tall trees." Does this have anything to do with epigenetics?

To some extent, Lamarck's theory is related to epigenetic inheritance, which emphasizes that environmental factors may affect the characteristics of organisms and may be passed on to offspring. However, the discovery of epigenetic inheritance does not mean that Lamarck's theory is correct.

Q2

What are the hot issues in epigenetic research at present?

1. How is epigenetic information inherited across generations?

2. What is the epigenetic mechanism by which a fertilized egg develops into an individual?

3. What are the new epigenetic modifications? What important proteins mediate the establishment and erasure of these epigenetic modifications?

Q3

What problems can be solved by studying epigenetics?

1. Improve the efficiency of somatic cell cloning and promote the development of stem cell technology.

2. Explain the mechanism of disease occurrence from the perspective of epigenetic mechanism and assist in the development of related drugs.

3. Realize the directed differentiation of stem cells and obtain specific types of cells.