Archive for ‘Epigenetics’

October 22, 2011

Worms with Genes for Long Life Pass on Longevity to Offspring…Even Without the Genes

Epigenetic changes in your parents’ chromosomes could affect your lifespan. At least, that is, if you’re a simple roundworm.

Recent research has shown that some epigenetic changes in plant DNA can be inherited. (See here, here). However, these changes aren’t robust, and tend to drop out after a few generations.

The epigenetic changes in plants that were heritable involved DNA methylation. The new research on roundworms (Caenorhabditis elegans) concerned a slightly different type of epigenetic change: methylation of a histone protein. Histones make up chromatin, the scaffolding around which DNA is wrapped around in chromosomes. There are four different histones, and two copies of each of these form a nucleosome. About 146 base pairs of DNA are wrapped around each nucleosome. The expression of genes whose DNA is wrapped around a nucleosome can be affected by the methylation state of the H3 histone.

Previous research had found that decreased levels of methylation of a specific part of the H3 histone resulted in longevity extensions of C. elegans by up to 30%. More specifically, a protein complex called H3K4me3 does the job of methylating the critical location in the H3 histone. Mutations of certain components of H3K4me3 were known to bring about the longevity extension effect.

How Longevity Is Passed On

Anne Brunet, an associate professor of genetics at the Stanford School of Medicine, found that mutations in a chromatin-modifying complex also significantly increased lifespan in C. elegans. The complex, known as the histone H3 lysine 4 trimethylation (H3K4me3) complex, is responsible for methylating a chromatin packaging protein called histone H3. This methylation is often associated with the increased expression of genes in the vicinity.

When Brunet and her colleagues knocked down members of the H3K4me3 complex—such as the WDR-5 and SET-2—they extended C. elegans life by up to 30 percent, suggesting that the epigenetic changes regulated by the complex controlled genes related to lifespan.

“Basically we think that the reason why those worms live longer is because they have less of this H3K4 mark at specific loci in the genome,” Brunet explained. “That probably results in changes in the expression of some genes,” such as those that regulate the aging process, she added.

That much was understood before the latest research. The new and rather surprising thing the new research has shown is that even if the mutations affecting H3K4me3 levels are eliminated in succeeding generations, the longevity extending effect persists for two more generations. The research found that expression of certain genes affecting metabolism – which often in turn affects longevity – persisted across generations, suggesting that other, as yet unknown, epigenetic changes occurred due to the original changes in H3 methylation.

The research paper itself concludes:

Our observations are consistent with the notion that H3K4me3 at specific loci may not be completely erased and replenished. Alternatively, the ASH-2/WDR-5/SET-2 complex could control the expression of the genes responsible for the erasure and replenishment of histone methylation marks between generations. Modulation of H3K4me3 modifiers in parents may also affect an unidentified protein or RNA that could in turn be inherited and cause lifespan changes.

Further reading:

Long life passed down through generations

Live long, pass it on

Worms with Genes for Long Life Pass on Longevity to Offspring…Even Without the Genes

Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans

October 3, 2011

Epigenetic clue to schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder are known to occur significantly more often in some families than in others, so some genetic component is rather likely. Particular genes that seem to be involved have even been identified. But at the same time, it often happens that in pairs of identical twins, having identical DNA, one twin may have the disorder while the other does not. So there must be other factors besides strict genetics involved – diet, lifestyle, stress, or infectious diseases, for example.

The task would then be to determine the mechanisms through which such environmental factors act. The mechanisms could still be genetic, if an environmental factor has epigenetic effects, as many do. One of the most studied epigenetic mechanisms is DNA methylation, in which a methyl group is added added at specific places within the DNA. In particular, if a spot in the promoter region for some gene is methylated, expression of the gene is inhibited. But if the methylation is removed, expression of the gene (which might be in a mutated form) is enabled.

The research reported here studied pairs of identical twins in which only one of the pair had schizophrenia or bipolar disorder (or both). Scans of the genomes of each twin found significant differences in methylation patterns occurring in the promoter regions of genes that had already been linked to the psychiatric disorder that was present.

Although that provides very strong indications of genes that might be targeted to relieve the disorder, the question of what environmental factors caused the differences in methylation still remains. This is especially of interest, since it’s known that methylation patterns can be inherited.

Epigenetic clue to schizophrenia and bipolar disorder – New Scientist

Regardless of which condition the twin had, the most significant differences, with variations of up to 20 per cent in the amount of methylation, were in the promoter “switch” for a gene called ST6GALNAC1, which has been linked with schizophrenia. Although the function of the gene isn’t fully established, it is thought to add sugars to proteins, which could alter the speed or specificity of their usual function.

The findings tallied with another study which involved screening post-mortem brain tissue from people who had had some form of psychosis. The researchers found differences of up to 25 per cent in methylation of the same gene compared with controls.

Further reading:

Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder

September 24, 2011

Epigenetic changes don’t last

We just learned that epigenetic mutations occur much more rapidly than DNA mutations, in a study of methylation changes in Arabidopsis. And now it turns out that such epigenetic changes don’t actually last all that long – also from a study of methylation in Arabidopsis. The thing is that a methylation event can occur much more easily than a change in DNA base sequences – and the event is also much more easily undone. The implication is that epigenetics probably isn’t so important for long-term evolution after all.

Epigenetic changes don’t last – Max-Planck-Gesellschaft

Scientists at the Max Planck Institute of Developmental Biology in Germany have now produced the first comprehensive inventory of spontaneous epigenetic changes. Using Arabidopsis, the workhorse of modern plant genetics, the researchers determined how often and where in the genome epigenetic modifications occur – and how often they disappear again. They found that epigenetic changes are many orders of magnitude more frequent than conventional DNA mutations, but also often short lived. They are therefore probably much less important for long-term evolution than previously thought.

Further reading:

Spontaneous epigenetic variation in the Arabidopsis thaliana methylome

September 17, 2011

Are genes our destiny? ‘Hidden’ code in DNA evolves more rapidly than genetic code, scientists discover

Molecular biologists have known for some time that the genetic code residing in an organism’s DNA is not the only determinant of the organism’s characteristics (its “phenotype“). Identical twin animals and humans, and clones of plants, have the same DNA as their counterparts – yet they are not identical to each other. Various factors can alter how the same DNA is expressed in corresponding cells of twins and clones. The study of these factors makes up the science of epigenetics.

One of the most important epigenetic mechanisms is DNA methylation, which is a chemical modification to individual DNA nucleotides. It is usually the addition of a methyl group to a cytosine base that is adjacent to a guanine base. In humans up to 90% of cytosine-guanine pairs may be methylated. Methylation usually has the effect of silencing genes if it occurs in a gene’s promoter region.

Methylation patterns can be inherited in successive generations of a plant or animal. However, not too surprisingly, small changes of the pattern can occur, since the normal DNA copying process doesn’t automatically reproduce the methylation. Nevertheless, once a mutation of the pattern has occurred in an egg or sperm cell, it can be passed on to later generations. An obvious question is about how the rate of such epigenetic mutations compares with that of mutations in the DNA itself.

New research has answered that question for Arabidopsis thaliana, a form of cress that is a popular model organism for plant biologists. As it happens, mutations of methylation sites occur a whole lot more often than DNA mutations – about 5 orders of magnitude more often.

Are genes our destiny? ‘Hidden’ code in DNA evolves more rapidly than genetic code, scientists discover

The researchers discovered that as many as a few thousand methylation sites on the plants’ DNA were altered each generation. Although this represents a small proportion of the potentially six million methylation sites estimated to exist on Arabidopsis DNA, it dwarfs the rate of spontaneous change seen at the DNA sequence level by about five orders of magnitude.

This suggests that the epigenetic code of plants – and other organisms, by extension – is far more fluid than their genetic code.

Even more surprising was the extent to which some of these changes turned genes on or off. A number of plant genes that underwent heritable changes in methylation also experienced substantial alterations in their expression – the process by which genes control cellular function through protein production.

Further reading:

Transgenerational Epigenetic Instability Is a Source of Novel Methylation Variants