September 21, 2021

I, Science

The science magazine of Imperial College

If all of the cells in the human body contain exactly the same genes, then why don't all of our body parts look exactly the same? ...

If our cells did what they wanted to, we would double in size about every hour and be spherical. We’re told at school that every cell in the human body contains exactly the same genetic information, the same 46 chromosomes with the same genes. Why, then, are our cells not all the same? If they all have the same instructions, then surely every cell is instructed to biochemically build exactly the same machinery?

DNA & Beyond copy

Thankfully we are not spherical blobs of indistinct cellular mass. This because the idea that DNA is some inert, static, unmoving and unchanging molecule is wrong: DNA is dynamic, it moves, it stretches, it winds and unwinds. It changes. Your DNA is not the same in every cell, and it is these differences that allow you to develop so many different types of tissue, whether it be muscle, nervous or sensory.

Right from the start, right from the single celled egg, changes to DNA mean that when cells divide, a front, back, left, right, up and down can be formed. For example, in C. elegans (a well-studied much-loved nematode worm), a front is defined by the entry point of the sperm. The sperm enters the egg and releases its DNA. This genetic material meets with the maternal DNA and forms the new complete nucleus. However, the sperm also contributes a specialised structure called the centrosome. The sperm centrosome locally inhibits the actin network (a system of strands that maintain cell shape) at the entry point, causing the actin to ping like the skin of a balloon onto one side of the embryo, thus breaking the symmetry of the egg and giving direction.

With actin strands on one side and not on the other, different proteins in the cell stick differentially to the new ‘front’ and ‘back’ of the cell. These proteins then land on the DNA itself and affect gene expression – giving a head end and a back end which are genetically different. This means that every time the cell divides, the DNA will find itself in a cell with a specific protein content, in a particular signaling environment, which allows it to make the appropriate cell type, saving both you and everything else from amorphous blobbery.

The featured fluorescent microscope image (courtesy of Dr Edwin Munro) shows the C. elegans embryo during the first cell division. The actin network can be seen in red, DNA in blue and microtubules (responsible for separating the DNA into two new daughter cells) in green. The red actin is localized along the periphery of the anterior, thus defining it as the ‘front’.

It must be emphasised that it is not the DNA base pair code that is altered during the course of development and cell differentiation. Instead it is the way in which the DNA is folded, what chemical groups are stuck on the DNA itself, and the specific proteins bound on the DNA, that alter which genes are expressed and thus which protein machinery will be made in a cell. This aspect of genetics is called epigenetics. ‘Epi’ is Greek for over, around, outside. The study of epigenetics allows us explore over and beyond our genetic code.

To understand what sort of influence the genomic epigenetic state has on development, we can take a look at what happens when things go wrong. There are many documented instances of women giving birth to what is called an .ovarian teratoma – a mass of tissue containing random assemblages of organs, such as eyes, teeth, hair or rudimentary beating hearts, in a disorganized lump. Other reports have occurred where women miscarry with what is called a hydatidiform mole; a disorganized lump of placental tissue.

These epigenetic malfunctions tell us a lot about the importance of mammalian epigenetics for development. Right from the start, when the maternal and paternal chromosomes meet in the zygote, they already have a sex-specific epigenetic state. This manifests itself (partly) as differentially placed methyl groups present on the DNA. This means that the chromosomes are methylated at different points along the DNA chains depending on whether they are donated by the mother or father. Chromosomes from each parent in the zygote therefore have different gene expression, due to their sex-specific methylation statuses (and thus epigenetic identity).

The ovarian teratoma is an instance of all chromosomes having a female epigenetic identity, and a hydatidiform mole is formed when all the chromosomes have a male epigenetic identity. From this we learn that an altered epigenetic identity of the chromosome (without any changes to the DNA sequence) can have devastating effects on cell fate during development.

While the formation of hydatidiform moles and ovarian teratomas are relatively rare occurrences leading to inviable progeny, many people live with conditions involving an incorrect sex-specific epigenetic state of a single chromosome or region of a chromosome. Symptoms of such conditions vary widely, ranging from uncontrollable eating to mental disability.

We now know that aspects of your diet and lifestyle can affect the epigenetic state of your eggs or sperm, leading to altered development of your offspring. Folate deficiency can cause spina bifida, and maternal smoking can lead to reduced birth-weight and psychological problems. In fact, parental nutrition, stress, activity levels, depression and much more have been linked to altered DNA methylation in offspring. And what’s more, these alterations are heritable.

Epigenetics as a field is enormous and seems to be growing indefinitely, which is necessary as it is integral to biology. The DNA in our cells is so much more complex than previously imagined, and the more we learn the more questions arise. Scientists are now discovering the myriad of ways in which the epigenetic state of our DNA allows us to develop, respond to our environment and affect our offspring in previously unimagined ways.


IMAGE: Munro Lab