We inherit our parents’ genes, but what about epigenetics?
Epigenetic marks are chemical modifications of DNA that activate or silence certain genes. They are passed on when cells divide, but can they be passed on between 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 on its own, because its information must be interpreted by proteins present in the cell nucleus, which add additional information known as epigenetic information (“epi” comes from the Greek prefix meaning “above”).
With each generation, we inherit the DNA contained in the chromosomes of both our parents—23 chromosomes from our mother and 23 from our father—resulting in the 46 chromosomes typical of the human species (this number varies by species) in each of our cells. During development, our cells divide a very large number of times to form adult individuals (consisting of more than 30,000 billion 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 one differentiates to produce the variety of tissues and organs that make up our body. It is precisely epigenetic information that enables this differentiation.
"Bookmarks" in our genome
What do we know about these epigenetic mechanisms, which have been the subject of intensive research since the beginning of the century? They involve a large number of cellular factors, the functions of which we are beginning to understand. Within chromosomes, negatively charged DNA wraps around positively charged proteins called histones. Hundreds of factors bind directly to the DNA or to the histones, forming what could be described as an “epigenetic sheath.”
This sheath is far from homogeneous. It contains factors that can attach small molecules to the DNA molecule or histones; these molecules act like “bookmarks” that one might place in a book at specific locations. These are the well-known “epigenetic marks” (methylation, acetylation, etc.), and many of them are found on genes located along our chromosomes. These marks are essential; they differ among the various cell types that make up an organism and directly contribute 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 silenced in those cells). 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—that is, reproduce the expression of their unique set of genes—to their daughter cells. A major upheaval occurs during mitosis, involving significant regrouping and condensation of the chromosomes and, consequently, of the DNA they contain. During this stage, the DNA remains wound around histones, but many proteins in the chromatin complex are dissociated from it. However, most of the marks on the DNA and histones are preserved. Thus, epigenetic marks will remain on and around the DNA. Once mitosis is complete, these marks will enable the daughter cells to rapidly reconstruct the architecture of the genes along the chromosomes, which will still carry the essential epigenetic marks and will once again be able to recruit the factors associated with their function. 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, which fuse during fertilization to form the embryo’s first cell. This cell will divide to give rise to the various 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 extensively reprogrammed, as if the organism were striving 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 factors could influence future generations.
Specific examples of the effect of the environment on epigenetic regulation have been described in numerous animal and plant species.
In reptiles, temperature is a major determinant of sex, through the establishment of specific epigenetic marks (histone methylation). In insects, many phenotypic traits are linked to dietary regimens that lead to epigenetic variations, such as 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 indeed 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 the transmission of epigenetic states across generations are currently well documented in the nematode C. elegans and in plants—organisms in which there is less reprogramming of the epigenetic state during fertilization. Our team is working with the model organism Drosophila melanogaster, or the fruit fly. Following disruptions in the 3D organization of chromosomes, we have been able to demonstrate cases of the inheritance of epigenetic modifications on a gene responsible for eye color over many generations.
In the mouse model, studies have also shown that the insertion of genetic elements can induce epigenetic changes, particularly DNA methylation. These modifications lead to the repression of a gene responsible for coat color or of important metabolic genes which, when silenced, cause obesity or hypercholesterolemia—effects that are heritable across several generations.
In these examples of transgenerational inheritance, the initial signal that triggers an epigenetic change involves the modification of a short DNA sequence. Even if this sequence is restored to its normal state, the change persists. Although these phenomena are likely rare and may be influenced by genetic background, they could occur in nature. Further research will be needed to understand whether other epigenetic mechanisms could be inherited.
Although these findings do not alter current genetic laws, they suggest that, beyond the simple duplication and transmission of the DNA sequence to male and female gametes, epigenetic information may contribute to the inheritance of certain traits in many species. This research could therefore help us 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, CNRS Research Director, University of Montpellier
This article is republished from The Conversation under a Creative Commons license. Readthe original article.