We inherit our parents' genetics, but what about epigenetics?
Epigenetic marks are chemical modifications to DNA that activate or deactivate certain genes. They are reproduced when cells divide, but can they be reproduced between two generations?
Frédéric Bantignies, University of Montpellier and Giacomo Cavalli, University of Montpellier
As the basis of genetic information, DNA is the fundamental molecule of life on Earth. However, it cannot function alone, as its information must be interpreted by proteins present in the cell nucleus, adding additional information known as epigenetic information ("epi" comes from the Greek prefix meaning "above").
With each generation, we inherit DNA contained in the chromosomes of both our parents, in the form of 23 chromosomes from the mother and 23 chromosomes from the father, resulting in 46 chromosomes of the human species (this number varies depending on the species) in each of our cells. During development, our cells divide a very large number of times to form adult individuals (made up of more than 30 trillion cells!).
The equation seems relatively simple, because the DNA sequence of the 46 chromosomes is copied identically (during "DNA replication") before being divided equally between two "daughter" cells during each cell division (called "mitosis"). Despite this identical genetic information, our cells are not all the same. Each of them differentiates to produce the variety of tissues and organs that make up our body. It is precisely epigenetic information that allows this differentiation.
"Bookmarks" in our genome
What do we know about these epigenetic mechanisms, which have been the subject of intense research since the beginning of the century? They involve a large number of cellular factors, whose function we are beginning to understand. Within chromosomes, negatively charged DNA wraps around positively charged proteins called histones. Hundreds of factors bind directly to DNA or histones to form what could be described as an "epigenetic sheath."
This sheath is far from homogeneous. It contains factors that can deposit small molecules on the DNA molecule or histones, which act like "bookmarks" that could be placed in a book at specific locations. These are the famous "epigenetic marks" (methylations, acetylations, etc.), many of which are found in the genes located along our chromosomes. These marks are essential; they differ in the different cell types that make up an organism and contribute directly to the regulation of gene expression (for example, genes important for liver function will be expressed in liver cells, while genes specific to neurons or muscle cells will be switched off). The question now is whether these epigenetic mechanisms also influence the transmission of genetic information.
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Let's first consider the simplest case of mitosis (cell division). Most cells must pass on their function, i.e., reproduce the expression of their specific set of genes in their daughter cells. A major upheaval occurs during mitosis, with significant grouping and condensation of chromosomes and therefore of the DNA that composes them. During this stage, the DNA remains wrapped around histones, but many proteins in the sheath are dissociated from it. However, most of the marks on the DNA and histones are retained. Thus, epigenetic markers remain on and around the DNA. Once mitosis is complete, these marks enable the daughter cells to quickly rebuild the architecture of the genes along the chromosomes, which will still carry the essential epigenetic marks and will be able to recruit the factors associated with their function once again. Epigenetic mechanisms therefore play a direct role in the inheritance of cellular function.
Could this epigenetic information also be passed on to future generations? If so, the challenge is much greater. The information must be transmitted to the male and female gametes that fuse during fertilization to form the first cell of the embryo. This cell will divide to form the different cell types of the future organism. The stages of chromosome reorganization and condensation are even more drastic here than during mitosis. DNA methylation, histone marks, and the 3D organization of chromosomes are largely reprogrammed, as if the organism were trying to erase the epigenetic baggage accumulated in the previous generation.
Epigenetic transmission in certain species
Can epigenetics nevertheless influence the genetic inheritance of offspring? Today, this question is the subject of intensive, and sometimes controversial, research. This research aims in particular to understand whether environmental, nutritional, stress-related, or chemical or physical exposure factors could influence future generations.
Specific examples of the effect of the environment on epigenetic regulation have been described in many animal and plant species.
In reptiles, temperature is a major determinant of sex type, via the deposition of specific epigenetic marks (histone methylation). In insects, many phenotypic traits are linked to diets that cause epigenetic variations, for example the distinction between the queen and worker bees or the distinction between worker castes in certain ants (via DNA methylation and histone acetylation, respectively).
Exposure to chemical factors such as arsenic or bisphenol A can also cause epigenetic changes. Researchers are currently trying to understand the mechanisms by which these stimuli act and whether they can generate stable inheritance across generations in humans. Epidemiological studies have attempted to establish links between diet and its influence on offspring, but these studies often face multifactorial issues that are difficult to control and suffer from a lack of molecular evidence.
Studies using model organisms are therefore necessary to investigate the influence of epigenetic modifications on the transmission of genetic information. Examples of epigenetic state transmission across generations are currently well described in the worm C. elegans and in plants, organisms in which there is less reprogramming of the epigenetic state during fertilization. Our team is working on the model organism Drosophila melanogaster, or fruit fly. Following disruptions to the 3D organization of chromosomes, we were able to identify cases of inheritance of epigenetic modifications on a gene responsible for eye color over many generations.
In mouse models, studies have also shown that inserting genetic elements can induce epigenetic changes, particularly DNA methylation. These modifications lead to the repression of a gene responsible for coat color or important metabolic genes which, when suppressed, cause obesity or hypercholesterolemia, and this can be inherited over several generations.
In these examples of transgenerational inheritance, the initial signal that induces epigenetic change involves the modification of a small DNA sequence. Even if this sequence is restored to normal, the change persists. Although probably rare and possibly influenced by genetic heritage, these phenomena could exist in nature. Future research will be needed to understand whether other epigenetic mechanisms could be inherited.
Although these findings do not change current genetic laws, they indicate that, beyond the simple duplication and transmission of DNA sequences to male and female gametes, epigenetic information could contribute to the inheritance of certain traits in many species. This research could therefore be used to better understand the evolution and adaptation of species, as well as the mechanisms underlying certain human diseases, such as cancer.
Frédéric Bantignies, Director of Research , University of Montpellier and Giacomo Cavalli, Director of Research at CNRS, University of Montpellier
This article is republished from The Conversation under a Creative Commons license. Readthe original article.