A breakthrough study has revealed that sex chromosomes, especially through the genes ZFX and ZFY, play a key role in regulating gene expression throughout the human body, challenging conventional wisdom about their function. Sex chromosomes in humans originate from a pair of autosomes, i.e., common chromosomes or non-sex chromosomes, which contain most of our genome and come in pairs.
The ancestors of this pair of autosomes differentiated into two different chromosomes – x and y, and although x and y have been separated from each other and have a unique function – i.e., determining sex and driving the sex differences between males and females – they also retain the shared functions inherited from a common ancestor.
Recent research by David Page (D**ID Page), a member of the Whitehead Research Institute and a professor of biology at the Massachusetts Institute of Technology and a Howard Hughes medical fellow, and Adrianna San Roman, a postdoctoral fellow in his lab, reveals the combined role of sex chromosomes as influential gene regulators.
The study, published Dec. 13 in the journal Cell Genomics, shows that genes expressed on the X and Y chromosomes affect cells throughout the body, not just those in the reproductive system, and they turn up or down the expression of thousands of genes on other chromosomes.
Karyotype of the full set of human chromosomes. Source**: National Human Genome Institute.
ZFX and ZFY: key gene regulators
In addition, the researchers also found that a pair of genes responsible for about half of the regulatory behavior—ZFX and ZFY—are located on the X and Y chromosomes, respectively, and that they have essentially the same regulatory role. This suggests that ZFX and ZFY inherited their role as influential gene regulators from their common ancestors and maintained this role independently, even when their respective chromosomes diverged, as this regulatory role is essential for human growth and development. Genes regulated by ZFX and ZFY are involved in a variety of important biological processes, suggesting that sex chromosomes contribute a wide range of functions in addition to those associated with sexual characteristics.
The influence of sex chromosomes on gene expression worldwide
Peggy and Sang Roman measured how the X and Y chromosomes affect overall gene expression by plotting how the expression of each gene in a cell changes with changes in the number of X or Y chromosomes. In this study, they used tissue samples from people with natural variations in the number of sex chromosomes: these people were born with one to four X chromosomes and zero to four Y chromosomes. These sex chromosome variants are ubiquitous in humans, and they cause a variety of health diseases, but unlike most other chromosomal duplications, they are compatible with life.
By taking advantage of the natural variation in the composition of sex chromosomes in human populations, we are able to mathematically model how the number of X and Y chromosomes affects gene expression in a way that has never been done before. Through this approach, we have gained new insights into the dramatic impact that the X and Y genes have across the genome"。Sang Roman said.
In this project, the researchers studied two cell types – lymphoblasts (a type of immune cell) and cell-derived fibroblasts (which help form our connective tissue) – and they selected both cells for ease of sample acquisition and measured how gene expression in each cell type changed with the appearance of each additional X or Y gene.
They found that thousands of genes change their expression levels as the number of X and Y chromosomes changes. These effects are linearly proportional, meaning that with each additional X or Y chromosome, gene expression changes to the same degree. Which genes are affected and to what extent for each cell type varies, suggesting that each cell type in the body may have a unique response to gene regulation of genes on both the X and Y chromosomes.
Through this approach, we have gained new insights into the enormous impact of the X and Y genes on the entire genome. "Sang Roman said.
Uncover the surprising similarities and differences in gene regulation
However, for specific genes in a particular cell type, the effects of the extra X gene tend to be similar to those of the extra Y gene. The discovery came as a surprise to the researchers, who thought that differences in the regulation of other genes in the X and Y genes might help explain some of the sex differences in health and disease. For example, men and women have different risks for certain diseases, have different symptoms when they have the same disease, and respond differently to certain medications. There are many differences between male and female cells that have not yet been explained, and gene regulators on x and y, which are modulating gene expression throughout the body, seem promising to lead to these differences.
Instead, Page and San-Roman narrowed down their study, and they found that a pair of genes, zfx and zfy, were responsible for about half of the effects of x and y on broad gene expression, and that the pair appeared to function comparably for genes—although zfx sometimes had a slightly stronger effect than zfy. Other genes on x and y may also be regulators of a wide range of genes, accounting for the other half of the impact.
These other gene regulators may be X-Y gene pairs, like ZFX and ZFY, and play essentially equivalent roles. After all, gene regulation is an important function, and the regulatory role that x and y inherit from a common ancestor may need to be achieved in exactly the same way to achieve fetal survival, regardless of how x and y grow separately.
However, researchers suspect that some X and Y genes must alter gene expression in different ways or to varying degrees to account for many of the sex differences that emerge in male and female cells**. The challenge is that because the strongest effects of the X and Y genes on a wide range of gene expression are common, it will be more difficult for researchers to figure out the different ways in which these two chromosomes affect gene expression.
Sang Roman said. "The effects on the genome may explain the sex differences, which are more subtle than what we have before. One point of interest in future research is that although we see a high correlation between the effects of x and y on gene expression, we observe that x has a greater effect relative to y copy number, which may be one of the reasons for the sex difference. "
Rethinking the Sex Chromosome: Inactive X vs. Active X
One subtlety that Page and Sang Roman have not discussed so far is that when Page and Sang Roman consider sex chromosomes, they no longer think about x as most people think. Their research work convinced them that our current understanding of sex chromosomes is not precise. While the sex chromosomes of humans are defined as X and Y, there are actually two types of X chromosomes, with only one difference between a typical male and a female. There is one for everyone in the world"Active X"Chromosome. This chromosome, like its own chromosome, is ubiquitous, so its presence is not related to sex.
Typical males and females differ in the chromosomes paired with the active X chromosome: a typical male has a Y chromosome, while a typical female has one"Inactive X"chromosome, which has the same genes as the active x chromosome, but most of the genes are turned off. In people with atypical sex chromosome composition, any extra X chromosomes will be inactive X chromosomes – so when researchers measure the effect of adding more X chromosomes, they are actually measuring the effect of adding more inactive X chromosomes.
The researchers found that the inactive x and y, rather than the x and y, more precisely, were sex chromosomes altering widespread gene expression. In addition, Page and Sang Roman also found that both inactive X and Y regulate the expression of many genes on the active X chromosome, as they do on all autosomes. (This is an extension of previous studies of the relationship between inactive x and active x). In summary, the active X chromosome behaves like an autosome, while the non-active X and Y chromosomes are two sides of the same coin, being both sex chromosomes and gene regulators.
Page said:"These chromosomes have historically been called'Inactive'and the X chromosome'Genetically poor'The Y chromosomes, apart from their contribution to sex differentiation, have received little attention, so we were shocked to see such a wide network of influences. These chromosomes contain genes like ZFX and ZFY, which are global gene regulators, and I think as we learn more about them, it will revolutionize the way we think about the genetics of the X and Y chromosomes in humans. "
Compilation**: scitechdaily