Epigenetics. © INRA, INRA

Livestock epigenetics: laying the foundation for future benefits

We all have genomes AND epigenomes

The epigenome comprises all the markers, or tags, that have been added to the genome; this process occurs without modifying DNA sequences. These tags regulate gene expression. Cells of different tissue types all contain the same DNA but have different epigenetic profiles, which explains how they become differentiated.

By Pascale Mollier, translated by Jessica Pearce
Updated on 07/10/2014
Published on 05/21/2014

“Mapping the pronuclei present in a 15-hour-old mouse embryo.” The mouse embryo underwent chemical fixation 15 hours after conception and was labeled with immunofluorescent proteins that reveal the different types of histone proteins present in the pronuclei. Pronuclei is the term used to refer to the sperm-derived nucleus and the egg-derived nucleus present in the 1-cell stage embryo. Here, they are located in the center of the embryo, whose exterior surface is visible in green. The embryo was viewed using a confocal microscope (Zeiss LSM 510; services provided by INRA platform MIMA2). The images obtained were processed using ImageJ software (http://rsb.info.nih.gov/ij/) and were recolored to yield the “mapping” effect. This image was part of the photography competition/exhibition on the theme “Arts and Science” that took place in Jouy-en-Josas in 2009.. © INRA, ADENOT Pierre, BEAUJEAN Nathalie, JEANBLANC M
“Mapping the pronuclei present in a 15-hour-old mouse embryo.” The mouse embryo underwent chemical fixation 15 hours after conception and was labeled with immunofluorescent proteins that reveal the different types of histone proteins present in the pronuclei. Pronuclei is the term used to refer to the sperm-derived nucleus and the egg-derived nucleus present in the 1-cell stage embryo. Here, they are located in the center of the embryo, whose exterior surface is visible in green. The embryo was viewed using a confocal microscope (Zeiss LSM 510; services provided by INRA platform MIMA2). The images obtained were processed using ImageJ software (http://rsb.info.nih.gov/ij/) and were recolored to yield the “mapping” effect. This image was part of the photography competition/exhibition on the theme “Arts and Science” that took place in Jouy-en-Josas in 2009. © INRA, ADENOT Pierre, BEAUJEAN Nathalie, JEANBLANC M

We have known since the 1950s (1) that the genome contains the units of heredity—genes—that determine our traits. The genome of a living organism is composed of coding DNA (2), noncoding DNA (3), and repeated or truncated sequences that are likely retroviral in origin.
However, a simple question then emerges: why do cells differ among tissue types since all cells contain the same genes? The answer to this question is lies in how gene expression is regulated: not all genes are expressed in all tissues at all times.

The epigenome is at the heart of cell identity

Several mechanisms are involved in gene regulation. The first mechanism to be discovered (4) was the action of regulatory proteins that control gene transcription. These proteins (5) attach themselves to promoter sequences or regulatory sequences, which are often located upstream of the genes to be transcribed.

Since the 1990s, a complementary mechanism has been described. It involves the chemical modification of either DNA or histones (6): a chemical marker is added via such processes as methylation or acetylation. These markers, which are called epigenetic tags, activate or inhibit gene expression. It is the totality of these tags added to the genome that make up the epigenome. Epigenetic tags regulate the expression of genes without changing their DNA sequences.  

How does the epigenome get set up?

Each cell has its own epigenetic profile that determines which of its genes are expressed. When gametes (eggs and sperm) are formed, the tags inherited from their mother cells are removed and replaced by gamete-specific tags. The sperm cell’s DNA in particular is hypermethylated, and its histones are replaced by protamines, which turns off transcription during fertilization. However, the situation changes again after fertilization: the gametes’ tags are once more removed. This methylation-demethylation process is called epigenetic reprogramming. It is crucial for embryonic development. Animals whose methylation enzymes have been inhibited are unable to produce viable embryos.

In somatic-cell nuclear transfer, a common cloning technique, a nucleus from a differentiated somatic cell is placed in an oocyte, the nucleus is reprogrammed, and the new cell becomes totipotent: it can generate all the cell types needed by the embryo. The high failure rate of this cloning technique can be traced to defects in the methylation-demethylation cycle. Methylation differences also explain why clones may differ from each other, despite having the same genome: it is because their genes are not expressed in the same way. For instance, their coats may differ in color or they may differ in size.

Epigenome-based phenotypic plasticity as a response to environmental changes

The epigenetic profiles of cells can be modified, in ways that are more or less long-lasting, in response to environmental changes. Many studies have shown that diet, biotic stressors (e.g., illnesses), abiotic stressors (e.g., extreme temperatures or water scarcity), xenobiotics (e.g., diethylstilbestrol), and behavioral interactions can modify the epigenetic profiles of cells over the course of a month or a year and can lead to changes within the organism. The epigenome also plays an important role during development, as the fetus is affected by the maternal environment, including the effects wrought by such factors as the mother’s diet. We will delve into several examples of such situations in different sections of this report.  

Still so many unanswered questions

The number of possible epigenetic modifications remains unknown, and the effects of each modification, by itself or in tandem with others, are far from being fully characterized. Furthermore, the mechanisms that add epigenetic tags to the genome are only partially described. It is known that specific enzymes, such as DNA-methylases, phosphorylases, and acetylases, are involved. However, we don’t know how the genes that code for these enzymes are regulated nor have we identified the mechanisms that result in these enzymes acting on specific genomic regions.

What is the role of the small noncoding RNA molecules that are also involved in epigenome modifications?

We have only a rudimentary understanding of the epigenome; we know even less about the ways in which the epigenome is regulated at the genetic level!
 
(1) Experiments showing that DNA is the hereditary material: transformation of pneumococcus bacteria (1944) and research on bacteriophages (1952). In 1953, Watson and Crick described the double-helix structure of DNA.

(2) transcribed into messenger RNA, which is then translated into proteins.

(3) nontranscribed, or transcribed but not translated.

(4) The famous lac operon that earned François Jacob, Jacques Monod, and André Lwoff the 1965 Nobel Prize for Medicine.

(5) These proteins may demonstrate enzymatic activity, act as transcription factors, or remodel chromatin architecture. They also form large complexes that are associated with regulatory regions of the genome.

(6) Histones are the proteins around which DNA is wound; together, they form what is called the chromatin.

Epigenesis was already a hot topic in the 17th century

Waddington’s Epigenetic Landscape. C.H. Waddington (1957) The strategy of the genes, London, Allen and Unwin © Waddington
Waddington’s Epigenetic Landscape. C.H. Waddington (1957) The strategy of the genes, London, Allen and Unwin © Waddington

When William Harvey, an English physiologist and anatomist, coined the term “epigenesis” in 1651, we were still a long ways off from discovering the epigenome and its mechanisms. Harvey used epigenesis to refer to the progressive “appearance” of organs during development: he had dissected a large number of pregnant deer and had observed the different fetal stages. During this era, one of the rival theories was that adult animals contained tiny versions of all their progeny, tightly packed together. This intellectual controversy was not settled until the idea of the gene was introduced and a link was established between genetics and development. It was another Englishman, Conrad Waddington, who formally described the concept of the “epigenetic landscape,” between 1940 and 1950. The contours of the epigenetic landscape are fashioned by genes and their interactions with the environment. He proposed that once a cell has taken a particular path within this landscape, its fate is almost entirely sealed.

Waddington (1957) The strategy of the genes, London, Allen and Unwin

We are far more than the sum of our genes

“Our epigenomes—that is to say the way in which our genomes are expressed—allow us to hope that we are more than the just the sum of our genes, an idea that has elicited a great deal of interest and curiosity on the part of the general public and the media. Do we have the ability to partially escape the unavoidable destiny inscribed in our genes? Is it possible that the foods we eat, the air we breathe, and even the emotions we feel influence not only how our genes are expressed, but how the genes of our future children and grandchildren will be expressed?”

Excerpt from the inaugural lesson given by Edith Heard, chair of Epigenetics and Cellular Memory, at the Collège de France on Dec. 13, 2012.