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About Epigenetics

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With recent advances in genetics we are increasingly aware of disorders that are caused not by changes in the DNA sequence (DNA mutations) but rather by changes in some of the epigenetic modifications (epi-mutations) that can influence gene expression without a corresponding change in genome sequence. These disorders are in some ways very different from typical Mendelian diseases, as these can appear in unusual ways in families (i.e. discordant monozygotic twins), and unusual techniques are used to study them (such as DNA methylation analysis and SNP array looking for uniparental disomy). However, some Mendelian disorders are also expected to affect the epigenome, especially those which involve the machinery that maintains these marks. Since epigenetic marks are more flexible than DNA variation, we feel that it makes perfect sense to follow these conditions as a group to learn more about them and about possible therapeutic opportunities.

How can you conceptualize epigenetics?

One way to think about epigenetics is that it is like a highlighter of the human genome to help decide when and where to use some of the genes. Why do people think this? All cells in the body obviously have the same genetic material, yet they behave very differently based on what their cell type specificity is. For instance, a nerve cell acts very differently than a muscle cell. Epigenetic marks participate in highlighting the genetic material that is being used in the particular cell type.

What is epigenetics?

The term epigenetics is used to describe any alteration of the DNA, which does not affect the DNA sequence itself, but which is maintained through cell division. Here, we focus on DNA methylation and histone modifications. DNA methylation (and DNA hydroxymethylation, a more recently discovered modification) are changes that involve the addition of a methyl group to cytosines in the DNA. The impact of DNA methylation differs based on context, but in some instances it can affect the expression of a parental allele (for instance in genomic imprinting, see below). DNA methylation is the epigenetic modification that has been most studied, and there are currently laboratory tests available to study this modification (DNA methylation analysis of critical regions of genomic imprinting).

What is genomic imprinting?

Genomic imprinting refers to the differential expression of alleles, depending on the parent of origin. It is quite amazing that for imprinted genes, the two copies (one from mom and one from dad) remember from which parent they came!!!! When this pattern is disrupted, imprinting disorders result. The figure below (see Figure 2) shows a pair of chromosomes, which contain an imprinted region, the red being the copy that came from the mother and the blue the copy that came from the father. In this example, the gene is only expressed from the maternal copy. There is increased methylation of the critical region (the differentially methylated region or DMR) on the paternal allele, resulting in decreased or loss of expression of that copy. Imprinting disorders can occur when an individual has a deletion of one of the copies, when an individual has received two copies from one parent (uniparental disomy), and when the two alleles behave epigenetically as if they came from the same parent (because of a de novo epimutation or the incomplete erasure of the mark in a previous generation). In addition, even monozygotic twins (genetically identical) can sometimes be discordant for disease states. Occasionally, this discordance can be caused by different epigenetic modifications in the twins (an epimutation) and is uncannily common for some of our conditions (such as Beckwith Wiedemann syndrome).

What makes epigenetic conditions different from other conditions?

Epigenetic conditions are different than other conditions for several reasons:
1) Epigenetic marks are sensitive to the environment. For instance, children with imprinting disorders are more likely to have been conceived through artificial reproductive technology than other children.
2) Epigenetic conditions have been seen in discordant monozygotic twins.
3) Epigenetic conditions can be caused by uniparental disomy (i.e. the inheritance of the two copies of a chromosome from a single parent).
4) Imprinting disorders can be caused by incomplete erasure of an epigenetic mark in a prior generation.
5) Imprinting disorders can be caused by abnormalities of several genes within a single domain rather than a single gene (Beckwith Wiedemann syndrome).
6) Epigenetic marks may be more malleable, and thus these conditions may be easier targets for future therapeutic development.

What are the Mendelian disorders of the epigenetic machinery?

Recently, a number of disorders have been found to result from abnormalities in genes encoding components of the histone machinery. These disorders, although genetic, will most likely have epigenetic consequences. However, unlike with imprinting disorders, which tend to involve a specific gene or localized genomic region, mutations in critical components of the epigenetic machinery will be expected to affect the epigenetic marks of large numbers of genes throughout the genome and thereby their expression (see Figure 4 below). In the future, the epigenetic deficiency might be used as a biomarker to help predict prognosis. In addition, these flexibile epigenetic marks could be targeted for therapeutic development.

Are we studying any of these conditions?

One in which we are particularly interested is the prototypical Mendelian Disorder of the Histone Machinery: Kabuki syndrome. The human body has many different cell types, yet they all share identical information content. The human genome (the book of life), which is the encyclopedia of all the machinery in all the cells has about 20,000 genes (words). How does a cell decide which genes (words) to use at a specific time? One way is through the use of epigenetics. Particular epigenetic modifications associate with the genes (words) that they affect and thereby essentially highlight (or strikethrough) the genes (words) that should be used by that cell type at any given time.
Kabuki syndrome is a rare (1:30,000) Mendelian disorder of the epigenetic machinery where one of these highlighters is broken (a histone H3K4 trimethylating enzyme called MLL2). Patients with Kabuki syndrome have beautiful eyes, which reminded the doctors who first described this disease of the face painting in Kabuki opera. In addition to distinct facial features, our patients with Kabuki syndrome have congenital heart disease and intellectual disability. Since the highlighting function is an ongoing activity in cells, it is much more reversible than a typical genetic mutation. By affecting the balance between highlighters and erasers we hope to be able to develop a therapy for the intellectual disability seen in this disease, even if patients are diagnosed after the first few years of life when most of the neurons have formed.

What are the Mendelian disorders of the epigenetic machinery?

Recently, a number of disorders have been found to result from abnormalities in genes encoding components of the histone machinery. These disorders, although genetic, will most likely have epigenetic consequences. However, unlike with imprinting disorders, which tend to involve a specific gene or localized genomic region, mutations in critical components of the epigenetic machinery will be expected to affect the epigenetic marks of large numbers of genes throughout the genome and thereby their expression (see Figure 4 below). In the future, the epigenetic deficiency might be used as a biomarker to help predict prognosis. In addition, these flexibile epigenetic marks could be targeted for therapeutic development.


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