- Describe examples of gene regulation through DNA methylation and mechanisms of genomic imprinting. Explain how methyltransferases allow methylation to be heritable.
- Explain how DNA methylation can be associated with monoallelic expression.
The term epigenetics describes any heritable change in phenotype that is not associated with a change the chromosomal DNA sequence.
Originally it meant the processes through which the genes were expressed to give the phenotype; that is, the changes in gene expression that occur during normal development of multicellular organisms. This includes the change in transcriptional state of a DNA sequence (gene) via DNA or chromatin protein reversible modifications. Thus, DNA methylation and histone protein methylation, phosphorylation, and acetylation have been targeted as mechanisms for heritable changes in cells as they grow from a single cell (zygote) and differentiate to a multicellular organism. Here, dividing cells commit to differentiate into different tissues such as muscle, neuron, and fibroblast due to the genes that they express or silence. Some genes are irreversibly silenced, through epigenetic mechanisms, in some cell types, but not in others. This doesn’t involve any change in DNA sequence.
Remember, these epigenetic effects are not permanent changes and thus cannot be selectable in an evolutionary context. However, mutations in the genes that regulate the epigenetic effect can be selected.
Epigenetics describes any heritable change in phenotype that is not associated with a change in the chromosomal DNA sequence.
Heritability of epigenetic modifications
During DNA replication, parental strands are used as a template to create complementary strands. However, modified bases or histones are not copied directly. Instead, cells have enzymes that recognize partially modified DNA and add modifications to the newly synthesized DNA. One example of an enzyme that plays this role is DNMT1 (DNA methyltransferase 1). When chromosome with methylated DNA is replicated, the parental strand retains the methylation, but the new strand does not, resulting in hemi-methylated DNA. Recall that DNA methylation usually occurs at CpG sequences, such that a CpG also exists on the complementary strand at the same position. DNMT1 recognizes hemi-methylated DNA and adds the corresponding methyl group to the new strand.
Researchers have found many cases of environmentally induced changes in gene expression that can be passed on to subsequent generations – a multi-generational effect. These altered expression patterns represent the diversity of expression for a genome. This extended phenotype, the ability to influence traits in the next generation, is a topic of current research and only some examples will be discussed here.
Epigenetics and maternal care
Watch this introductory video about experiments that tested the relationship between maternal care and offspring in rats.
In experiments, Meaney and colleagues examined the influence of maternal licking on epigenetic modifications of genes involved in stress. Previous studies had shown that maternal care was associated with reduced fear and stress responses in adult rats. To determine whether this effect was due to changes in gene expression, epigenetic modifications near the glucocorticoid receptor (GR) gene were examined. In rats raised by mothers exhibiting high licking-grooming behaviors, methylation of a CpG in the GR was absent and the region was associated with histone acetylation (Weaver et al, 2008). Both of these modifications are typically associated with active chromatin, or gene expression. This GR acts in a feedback loop to reduce some stress responses. Therefore, these findings are consistent with the rat behaviors with high levels of maternal care associated with higher expression of GR, reducing the stress response of adult rats. This example illustrates how the DNA nucleotide sequence of the offspring does not change, but their experiences and environments alters their gene expression profile and therefore their phenotype.
For some genes, the allele inherited from the oocyte is expressed differently than the allele that is inherited from the sperm. This pattern is distinct from sex-linkage and is true even if both alleles are wild-type and autosomal. During gamete development (gametogenesis), each parent imprints epigenetic information on some genes that will affect the activity of the gene in the offspring. Imprinting does not change the DNA sequence, but does involve methylation of DNA or histones, and generally silences the expression of one of the parent’s alleles. In humans, some genes are expressed only from the paternal allele, and other genes are expressed only from the maternal allele. The imprinting marks are reprogrammed before the next generation of gametes are formed. For example, a sperm-producing individual inherits epigenetic information from both and oocyte and sperm, but the epigenetic marks will be erased before sperm development and only one the sperm pattern of imprinting will be passed to his offspring, either male or female.
Because imprinting often produces monoallelic expression of a gene, if one copy is mutated or lost, phenotypic changes may be observed. This phenomenon produces an exception to Mendelian rules about recessive alleles not producing a phenotype when heterozygous.
Imprinted genes, of which there are currently about 100 genes in humans, appear to explain many parent-of-origin effects. For example, Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS) are two phenotypically different conditions in humans that result from deletion of a specific region of chromosome 15, which contains several genes. Whether the deletion results in PWS or in AS depends on the parent-of-origin. If the deletion is inherited from the father, PWS results. Conversely, if the deletion is inherited from the mother, AS is the result. The gene(s) involved in PWS is maternally silenced by imprinting, therefore the deletion of its paternally-inherited allele results in a complete deficiency of a required protein. On the other hand, the paternal allele of the gene involved in AS is silenced by imprinting, so deletion of the maternal allele results in deficiency of the protein encoded by that gene.
Transgenerational inheritance of nutritional influences
Nutrition is one aspect of the environment that has been particularly well-studied from an epigenetic perspective in both mice and humans. Adults who were conceived during the Dutch famine of 1944-1945 have IGF2 genes that are less methylated than their siblings born before or after the famine, even decades after birth (Heijmans et al, 2008). The IGF2 protein is a signaling molecule that promotes growth and cell division. Further research is ongoing to determine how much impact this change in methylation has on phenotypes.
A study of an isolated Swedish village called Överkalix provides an example of transgenerational inheritance of nutritional factors. Detailed historical records allowed researchers to infer the nutritional status of villagers going back to 1890. The researchers then studied the health of two generations of these villagers’ offspring, using medical records. A significant correlation was found between the mortality risk of grandsons and the food availability of their paternal grandfathers. This effect was not seen in the granddaughters. Furthermore, the nutrition of paternal grandmothers, or either of the maternal grandparents did not affect the health of the grandsons. It was therefore proposed that epigenetic information affecting health (specifically diabetes and heart disease) was passed from the grandfathers, to the grandsons, through the male line (Pembrey et al, 2006). At least one study has recently replicated this finding in an independent population from Uppsala, Sweden (Vågerö et al, 2021)
In mouse models, the agouti gene produces a signaling molecule that regulates pigment-producing cells and brain cells that affect feeding and body weight. Normally, agouti is silenced by methylation, and these mice are brown and have a normal weight. When agouti is demethylated by feeding certain chemicals (for example) or by mutating a gene that controls methylation, some mice become yellow and overweight. Although the nucleotide sequence of the gene remains unchanged, the methylation at the locus decreases, causing overexpression of the protein (review 4.4: Exceptions to simple dominance). Methylation of agouti and normal weight and pigmentation of offspring can be restored if their mothers are fed folic acid and other vitamins during pregnancy.
Vernalization as an example of epigenetics
Many plant species in temperate regions are winter annuals, meaning that their seeds germinate in the late summer, and grow vegetatively through early fall before entering a dormant phase during the winter, often under a cover of snow. In the spring, the plant resumes growth and is able to produce seeds before other species that germinated in the spring. In order for this life strategy to work, the winter annual must not resume growth or start flower production until winter has ended. Rhe requirement to experience a long period of cold temperatures prior to flowering is called vernalization.
How does a plant sense that winter has passed? The signal for resuming growth cannot simply be warm air temperature, since occasional warm days, followed by long periods of freezing, are common in temperate climates. Researchers have discovered that winter annuals use epigenetic mechanisms to sense and “remember” that winter has occurred.
Fortunately for the researchers who were interested in vernalization, some varieties of Arabidopsis are winter annuals. Through mutational analysis of Arabidopsis, researchers found that a gene called FLC (FLOWERING LOCUS C) encodes a transcription repressor acting on several of the genes involved in early stages of flowering (Michaels and Amasino, 1999). In the fall and under other warm conditions, the histones associated with FLC are acetylated and so FLC is transcribed at high levels; expression of flowering genes is therefore entirely repressed. However, in response to cold temperatures, enzymes remove methyl and acetyl groups from the histones associated with the FLC locus. The longer the cold temperatures persist, the more acetyl groups are removed, until finally the FLC locus is no longer transcribed and the flowering genes are free to respond to other environmental and hormonal signals that induce flowering later in the spring. Because the deacetylated state of FLC is inherited as cells divide and the plant grows in the early spring, this is an example of a type of cellular memory mediated by an epigenetic mechanism.
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Contributors and Attributions
Dr. Todd Nickle and Isabelle Barrette-Ng (Mount Royal University) The content on this page is licensed under CC SA 3.0 licensing guidelines.