EPIGENOMICSNature vs. Nurture

Once nurture seemed clearly distinct from nature. Now it appears that our diets and lifestyles can change the expression of our genes. How? By influencing a network of chemical switches within our cells collectively known as the epigenome.

This new understanding may lead us to potent new medical therapies.

Epigenetic cancer therapy, for one, already seems to be yielding promising results.

Epigenetic treatment of mental illness is just around the corner.

 

Nature vs. Nurture

What is an Epigenom?

An Epigenome consists of a record of the chemical changes to the DNA and histone  proteins of an organism.These changes can be passed down to an organism's offspring.

For the most part, every cell in our body contains exactly the same genes, but inside the individual cells some genes are activated while others are silenced.

When genes are active they are capable of being translated into proteins. When genes are silent, they are inaccessible for translation into proteins.

Active and Silenced Genes

Some genes, like the Foxp2 gene, are only turned on during the early months of human development and then silenced via epigenetic mechanisms.

Some Genes Are Active Only During Early Development

For example the Foxp2 gene controls the wiring of the speech areas in the developing brain.

Mutations in the FOXp2 gene cause developmental verbal dyspraxia. These individuals have no developmental delays, but are unable to perform the coordinated movements required for speech.

Epigenomics is the science of activating or silencing genes at the level of transcription or translation.

A Silenced Gene is not Transcribed, Translated, or Expressed

Genes can be activated or silenced :

-By modifying the histone proteins (H3 or H4)

-By modifying the DNA (methylation at CpG promoters)

-By small interfering RNAs

According to some also

-By genomic imprinting

Silencing or Activating Genes

Modifications of Histone Proteins

Histones are DNA binding proteins that act as spools that keep the DNA in coils.

There are Eight Histone Proteins in Each Nucleosome

Histone 3 and 4 can be modified by methylation.

Methylation of DNA at CpG Sites

Methylation keeps the histones tight together. In this state the DNA cannot be transcribed/expressed. In order to be transcribed and expressed the histones must come apart by either demethylation or acetilation.

In Fragile X Syndrome FMR 1 Gene is Methylated

Fragile X Syndrome is caused by an expanded CGG trinucleotide repeat in the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing (by methylation) and loss of expression of the Fragile X Mental Retardation Protein (FMRP).

Normal FMRP is present on everyone’s X chromosome. It plays a role in: Synaptic protein synthesis Synaptic plasticity Dendritic spine formation Neuronal plasticity

In fragile X syndrome theFMRP is not expressed, thus nonexistent.

Fragile X Syndrome is an X-linked condition associated with intellectual disability, hyperactivity, attention deficits, anxiety and autistic-like behaviors.

Fragile X Mental Retardation Protein(FMRP)

Genes Can be Silenced by RNA Interference

RNA interference - gene silencing by small non-coding RNAs.

The non-coding RNAs interferewith protein synthesis machinery of the cell, silencing a gene.

Manipulation of RNA Interference Could Help Huntington’s Disease Patients

Huntington’s disease is a result of what is called an expanded “triplet repeat” in the huntingtin gene sequence.

RNA Interference technique could epigenetically silence the mutated gene, thus eliminating the translation of the CAG triplet repeat.

Genetic Imprinting - For some genes, only one copy is expressed and the other one silenced, depending on whether the gene is maternal (comes from the mother) or paternal (comes from the father).

Normal development requires one copy of certain genes from each parent.

Imprinting does not occur on every chromosome; only nine chromosomes are known to have regions of genes that are imprinted.

Imprinting occurs by a pattern of methylation, meaning the copy of the gene to be inactivated is coated with methyl groups.

Imprinting takes place before fertilization, in the egg and sperm cells.

Genetic Imprinting

Imprinting Deactivates Certain Genes By Methylation

Prader- Willi and Angelman syndromes are uniparental disomies (both copies of the genes on chromosome 15 come from the same parent).

Chromosome 15 regulates numerous neurologic and musculoskeletal structures and functions that affect intelligence, cognition, behavior, emotion, muscle tone, and metabolism.

When both copies of chromosome 15 are maternal (called paternal

deletion), genetic imprinting produces a constellation of symptoms known as Prader-Willi syndrome.

When both copies of chromosome 15 are paternal (called maternal deletion), genetic imprinting produces a constellation of symptoms known as Angelman syndrome.

Imprinting Disorders

Mitochondrial DNA (mtDNA) is not wrapped around histone proteins. For this reason methylation or acethylation does not influence transcription.

Mitochondrial DNA does not contain introns which means that each one of its13 genes is translated into a protein.

HOWEVER:

The mitochondrion contains about 1200 proteins, thus the remainder of the mitochondrial proteins are encoded by the nuclear DNA and thus subject to epigenetic factors.

Mitochondrial DNA (mDNA) is not Subject to Epigenetic Factors

Mitochondria Contain Proteins Encoded by its Own DNA and Proteins Encoded by the Nuclear DNA

Mitochondria encoded proteins are not subject to epigenetic factors, but proteins encoded in the nuclear DNA (nDNA) are.

Epigenetic Factors Can Explain Susceptibility to Mental Illness

It is believed that early life stress can alter the epigenome and program some brain circuits, by making them vulnerabile to major psychiatric conditions.

Identical twin studies show a schizophrenia concordance rate of 48-60%.

If schizophrenia were a genetic disorder the concordance rate should be 100% .

Epigenetic Factors Can Explain Lower Than 100% Transmission of Schizophrenia in Identical Twins

The first systematic Genom- Wide DNA methylation study was published in September 2011 in Human Molecular Genetics.

This study showed that identical twins discordant for schizophrenia had a different metylation pattern.

The twins with schizophrenia presented with a hypometylated promoter in a specific locus on chromosome 17 as compared with the unaffected twin.

This explains why identical twins are not 100% concordant for schizophrenia.

(Human Molecular Genetics, Sept.9,2011. Epigenetic Clue To Schizophrenia & Bipolar Disorder).

Epigenetics of Schizophrenia