Chapter 4: Life As We Know It Now

Chapter 4: Life As We Know It Now

The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them.  Sir William Bragg

Every biological phenomenon has a physical basis. --- the epigenetic outcomes we’ve described are all a result of variations in expression of genes.

John Gurdon and Shinya Yamanaka showed us it’s not anything to do with changing the DNA blueprint of the cell. That remains intact and unchanged.

Skin cells --- replaced about every five weeks, Neurons ---- the neurons in the brain of an 85-year-old person are about 85 years of age.

Sticking a grape on DNA

Methylation

A bit like sticking a grape on a tennis ball.

This methylation reaction is carried out in our cells by one of 3 enzymes called DNMT1, DNMT3A, Dnmt3B. -----the DNMTs are examples of epigenetic writers. Enzymes that create the epigenetic code. Only add a methyl group to a C that is followed by a G. C followed by G is known as CpG.

This CpG methylation is an epigenetic modification, which is also known as an epigenetic mark.

The more methylated the injected DNA was the less transcription that occurred.

CpG islands → regions where there is a high concentration of CpG motifs are called CpG islands.--- in the promoter region.

Promoter→ are the stretches of the genome where the DNA transcription complexes bind and start copying DNA to form RNA.

MeCP2 (methyl CpG binding protein 2) → enzymes that add the methyl group to DNA have been described as writers of the epigenetic code. Vs. MeCP2 doesn’t add any modifications to DNA. its role is to enable the cell to interpret the modifications on a DNA region. → example of a reader of the epigenetic code.

MeCP2 binds to 5 methylcytosine in a gene promoter

1)     It attracts other proteins that also help to switch the gene off.

2)     It may also stop the DNA transcription machinery from binding to the gene promoter.

3)     This prevents mRNA messenger molecule from being produced. → where genes and their promoters are very heavily methylated, binding of MeCP2 seems to be part of a process where that region of a chromosome gets shut down almost permanently.  → DNA becomes incredibly tightly coiled up and the gene transcription machinery can’t get access to the base-pairs to make m RNA copies.

Skin cell, the pattern of DNA methylation is passed from mother cell to daughter cells. → DNMT1 can recognize if a CpG motif is only methylated on one strand. → it replaces the missing methylation on the newly copied strand. //material makes life. Just physical character makes life//

Miracle mice on youtube

Rett syndrome → around 1 year old autism + mental retardation, mutation in the MeCP2gene which means that they don’t produce a functional MeCP2 protein. --- reader of methylated DNA  --- reading the epigenetic code properly is very important  --- MeCP2 protein is really important in the brain.

If the mice were given a specific harmless chemical, the normal MeCP2 gene became activated. ----  clips of this on youtube ---- offer hope that we may be able to find new treatment for really complex neurological conditions.

DNA has a friend

DNA is intimately associated with proteins, and in particular with proteins called histones.

Histone octamer figure

Nucleus of cell is usually only about 10 microns in diameter 1/100 of millimeter and if DNA in a cell was just left all floppy and loose it could stretch for 2 metres.  → DNA is curled tightly around the histone octamers and these are all stacked closely on top of each other.

David Allis → histone proteins were chemically modified in cells. And that this modification increased expression of genes near a specific modified nucleosome.  → this histone modification was called acetylation.

Acetylation fig

More than 50 different epigenetic modifications to histone proteins → the pattern of modifications is referred to as a histone code.

Gene expression is rarely an on-off toggle switch; it’s much more like the volume dial on a traditional radio.

Histone code → pattern of histone modification is referred to as a histone code.  --- extraordinarily difficult to read.

Build a better mousetrap

Boots → the zygote is preloaded with certain proteins, mainly from the egg cytoplasm. These egg-derived proteins move into the nucleus and bind to target genes, which we’ll call Boots. --- they also attract a select few epigenetic enzymes to the Boots genes. --- they setup  longer-lasting modifications to the DNA and histone proteins of chromatin, also influencing how these Boots genes are switched on or off.

The Boots protein bind to the Divers genes, and switch these on.  ---- some of these Divers genes may themselves encode epigenetic enzymes, which will form complexes on members of the Slides family of genes and so on. --- mousetrap game  --- Oct4 protein binds to certain key genes, and also attracts a specific epigenetic enzyme  --- this enzyme modifies the chromatin and alters the regulation of that gene.

Kabuki syndrome--- a complex developmental disorder with a range of symptoms that include mental retardation, short stature, facial abnormalities and cleft palate.  --- mutations in MLL2 gene. --- MLL2 protein is an epigenetic writer that adds methyl groups to a specific lysine amino acid at position 4 on histone H3. –--- Patients with this mutation are unable to write their epigenetic code properly, and this leads to their symptoms.

Mutations on enzymes that remove epigenetic modifications, erasers of the epigenetic code. Makes human disease. --- mutations in a gene called PHF8, which removes methyl groups from a lysine at position 20 on histone H3, cause a syndrome of mental retardation and cleft palate.

In addition to these histone writers and erasers there are over 100 proteins that act as readers of this histone code by binding to epigenetic marks. These readers attract other proteins and build up complexes that switch on or turn off gene expression. This is similar to the way that MeCP2 helps turn off expression of genes that are carrying DNA methylation.

DNA methylation is a very stable epigenetic change. ---- keeping neurons as neurons and no teeth on our eyeballs. Vs. most histone modifications are much more plastic than this. A specific modification can be put on a histone at a particular gene, removed and then later put back on again.

This happens in response to all sorts of stimuli from outside the cell nucleus. The stimuli can vary enormously. In some cell type the histone code may change 1) in response to hormones. This include insulin signaling to our muscle cells, or estrogen affecting the cells of the breast during the menstrual cycle. 2) In the brain the histone code can change in response to addictive drugs such as cocaine, whereas in the cells lining the gut, 3) the pattern of epigenetic modifications will alter depending on the amounts of fatty acids produced by the bacteria in our intestines.

These changes in the histone code are one of the key ways in which nurture (the environment) interacts with nature(our genes) to create the complexity of every higher organism on earth.

Evolved such complex patterns of histone modifications to regulate gene expression. ---- the complexity allows sophisticated fine-tuning of gene expression. 

Every biological phenomenon has a physical basis.

John Gurdon and Shinya Yamanaka showed us it’s not anything to do with changing the DNA blueprint of the cell. That remains intact and unchanged.

Skin cells   replaced about every five weeks

Neurons the neurons in the brain of an 85 year old person are about 85 years of age.

Sticking a grape on DNA

Methylation

A bit like sticking a grape on a tennis ball.

Only add a methyl group to a C that is followed by a G. C followed by G is known as CpG.

This CpG methylation is an epigenetic modification,  which is also known as an epigenetic mark.

The more methylated the injected DNA was the less transcription that occurred.

CpG islands → regions where there is a high concentration of CpG motifs are called CpG islands.

Promoter→ are the stretches of the genome where the DNA transcription complexes bind and start copying DNA to form RNA.

MeCP2 → enzymes that add the methyl group to DNA have been described as writers of the epigenetic code.  MeCP2 doesn’t add any modifications to DNA. its role is to enable the cell to interpret the modifications on a DNA region. → example of a reader of the epigenetic code.

MeCP2  binds to 5 methylcytosine in a gene promoter

1)     It attracts other proteins that also help to switch the gene off.

2)     It may also stop the DNA transcription machinery from binding to the gene promoter.

3)     This prevents mRNA messenger molecule from being produced. → where genes and their promoters are very heavily methylated, binding of MeCP2 seems to be part of a process where that region of a chromosome gets shut down almost permanently.  → DNA becomes incredibly tightly coiled up and the gene transcription machinery can’t get access to the base-pairs to make m RNA copies.

Skin cell, the pattern of DNA methylation is passed from mother cell to daughter cells. → DNMT1 can recognize if  a CpG motif is only methylated on one strand. → it replaces the missing methylation on the newly copied strand. //material makes life//

Miracle mice on youtube

Rett syndrome → around 1 year old autism + mental retardation, mutation in the MeCP2gene which means that they don’t produce a functional MeCP2 protein.

If  the mice were given a specific harmless chemical, the normal MeCP2 gene became activated.

DNA has a friend

DNA is intimately associated with proteins, and in particular with proteins called histones.

Histone octamer figure

Nucleus of cell is usually only about 10 microns in diameter 1/100 of millimeter and if DNA in a cell was just left all floppy and loose it could stretch for 2 metres.  → DNA is curled tightly around the histone octamers and these are all stacked closely on top of each other.

David Allis → histone proteins were chemically modified in cells. And that this modification increased expression of genes near a specific modified nucleosome.  → this histone modification was called acetylation.

Acetylation fig

More than 50 different epigenetic modifications to histone proteins  → the pattern of modifications is referred to as a histone code.

Gene expression is rarely an on-off toggle switch; it’s much more like the volume dial on a traditional radio.

Histone code → pattern of histone modification is referred to as a histone code. 

Build a better mousetrap

Boots → the zygote is preloaded with certain proteins, mainly from the egg cytoplasm. These egg-derived proteins move into the nucleus and bind to target genes, which we’ll call Boots.

These changes in the histone code are one of the key ways in which nurture (the environment) interacts with nature(our genes) to create the complexity of every higher organism on earth. 

Methylation 

Acetylation  

Gene expression is rarely an on-off toggle switch; it’s much more like the volume dial on a traditional radio.  

Histone code → pattern of histone modification is referred to as a histone code.   

Build a better mousetrap 

Boots → the zygote is preloaded with certain proteins, mainly from the egg cytoplasm. These egg-derived proteins move into the nucleus and bind to target genes, which we’ll call Boots. 

These changes in the histone code are one of the key ways in which nurture (the environment) interacts with nature(our genes) to create the complexity of every higher organism on earth.