Epigenetics remains somewhat mysterious, but a new study has revealed how it regulates the genome. A researcher says that the discoveries may lead to identifying new drug targets.
The human genome is more than just a long string of DNA that is read from one end to the other to determine the proteins cells need.
The DNA is wrapped around itself, wrapped around proteins and folded into a complex and compact three-dimensional structure that can enable and disable access to genetic information through a process called epigenetics.
Researchers have known for decades that this epigenetic control of information exists in the genome, but how this system works has been an open question.
However, researchers have now solved part of this mystery in a new study that describes how epigenetic control is regulated and the implications for how the genetic profile is made available or hidden.
“We now have greater insight into how the cells read the epigenetic information that controls the genome and how this influences people’s health and the development of disease. Our discoveries may therefore be potentially significant for treating people with certain genetic disorders, since we can identify mechanisms that may be out of balance when a disorder develops,” explains a researcher involved in the study, Till Bartke, Deputy Director, Institute of Functional Epigenetics, Helmholtz Munich, Germany.
The research has been published in Nature.
DNA is wrapped around proteins
The research investigated how DNA is incorporated in the cells to provide or hinder access to the cell’s nuclear machineries that read and translate the genes in the DNA into proteins.
For example, the cells need to use many proteins and thus genes as the fetus develops, but some of these genes and proteins are no longer used after birth and are then switched off.
Conversely, some proteins are only used in a fully developed body and are therefore only switched on late in fetal development through epigenetic packaging. An important part of this packaging is how DNA is folded around the proteins called histones.
Various properties of histones, such as the amino acids they are made up of , can affect the folding of the DNA and thus the accessibility of the DNA.
“These properties can be modified. The histones also contain many modifications of their amino acids, and this affects the epigenetic control of the genetic information encoded in the DNA. Further, other proteins can bind to various modifications on the histones and read the so-called epigenetic code, including adding or removing modifications. The question we aimed to answer in this study is how these proteins are able to recognise modifications, including several modifications at the same time,” says Till Bartke.
Epigenetics is a dynamic process
Till Bartke explains that this entire process in a cell is dynamic and continuously changes, with DNA constantly being epigenetically regulated through various proteins being added or removed to make some parts of the genome accessible and other parts hidden.
Part of the DNA may only need to be read occasionally, for example in defending against disease, whereas other parts need to be read and switched off again regularly, such as during a circadian cycle.
Others must be switched on or off continually, and a third group is solely used for cell division.
“In addition, the environment in which we live and the food we eat exerts epigenetic influence. Although this is known, we have understood very little of how this machinery for structuring the cell’s ability to decode epigenetic modifications actually achieves this,” explains Till Bartke.
Created (epi-)genetic material in a test tube
To investigate this, the researchers created semisynthetic nucleosomes in test tubes. A nucleosome is the packaging of DNA around a core of eight histones.
The researchers wrapped a DNA strand around histones they made in bacteria. They also made various chemical modifications to the histone proteins in the nucleosomes to study the effects of combinations of modifications as they exist naturally in cells.
“We thus created from scratch various control mechanisms that are present in the genome. We made many different nucleosomes with different combinations of modifications,” says Till Bartke.
Proteomic profiling
The researchers incubated the modified nucleosomes with nuclear extracts that contain various proteins that can read modifications in epigenetic regulation.
The modified nucleosomes ensure that only proteins that can recognise exactly the individual modifications or combinations of modifications attach themselves to the nucleosome. These proteins were thereby isolated from the extracts.
The researchers characterised the individual proteins using multidimensional mass spectrometry and thus obtained insight into which proteins are associated with a modification or a combination of modifications.
“This provides a broad overview of the proteins involved in epigenetic regulation by binding to modifications or combinations of modifications on the nucleosomes,” explains Till Bartke.
Proteins can be target for new drugs
Till Bartke says that the discoveries are interesting for basic science but can also have clinical significance in treatments related to various diseases.
Some diseases, such as cancer or certain hereditary diseases, result from mistakes in epigenetic regulation and not errors in the genetic code.
These errors can occur if there are mutations in the proteins that control the modification of the genetic material, thereby making the genetic information in the DNA available or unavailable in the wrong way.
“We already know about diseases and disorders caused by defective variants of genes that make these epigenetic proteins that add modifications to the histones or remove them again. Improved knowledge of these proteins and their disease-specific genetic variants can enable the development of drugs to inhibit or replace them, which may help people with the diseases,” says Till Bartke, who adds that these types of medicine are already in use and more are being developed.
“Our research may help to identify even more relevant proteins as drug targets,” concludes Till Bartke.
