1/ Epigenetics means on top of genetics. The study of Genetics is all about the DNA. Its about how its structured and packaged. Epigenetics is about how Genes are expressed and regulated.
2/ We are born with our Genetics, but our Epigenetics is acquired by experiences and environmental exposure. I don't want to get too deep into epigenetics, but I think there are a few concepts that are important to understand.
3/ The first one is the process of gene methylation and gene silencing. Each gene has a promoter in front of the gene where the transcription factors bind and activate transcription of that gene.
4/ The promoter of the gene will often have Cytosine and Guanine rich regions called CpG islands. That stands for Cytosine, Phosphate, and Guanine. These CpG rich regions can become methylated.
5/ Methylation of these CpG regions of the promoter can come from environmental factors like UV exposure, chemicals, radiation, smoking and so many other things. This exposure can cause the methylation of the promoter and eventual silencing of the gene.
6/ The silencing of a gene plays a big role in understanding tumor genesis in cancer. The loss of tumor suppressor genes don't always come from a mutation of the DNA which renders them ineffective. It will often come from gene silencing by epigenetic forces.
7/ The second concept of epigenetics is the Acetylation and Deacetylation of the Histones which package the DNA.
8/ We learned in genetic that the DNA gets wrapped twice around each histone. While the DNA is packaged like this, it is transcriptionally inactive. The proteins and enzymes that do transcription can not access packaged genes.
9/ For a gene to be transcribed, it has to be exposed to the transcription machinery. This is controlled by acetylation or deacetylation of the histones.
10/ The DNA normally has a slight negative charge. The histone has a slight positive charge. They like to electrostatically bond to each other. By adding or removing a acetyl group to the tails of the histone, the charge can change allowing the DNA to be unwound.
11/ This is an important concept to understand as a gene needs to be exposed to be active. Some areas of the DNA are always inactive and densely packaged like round the centromere and the telomeres. There is no genes encoded in this region.
12/ One cell might have a gene active as it uses it all the time while another cell will keep that gene packaged as it never uses that gene. Each cell only uses genes specific to that cells role and functions.
13/ Some oncology drugs will target the acetylation or deacetylation of histones to suppress the transcription of genes in cancer.
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1/ There is a complex set of interactions that must go on between a tumor and its surroundings. It has to interact with the tissue cells, it needs nutrients, it needs oxygen, it needs to survive and proliferate in a hostile environment.
2/ One of the many things it has to achieve to exist and thrive is to overcome the immune system and its natural ability to find, target and destroy tumors. There are 3 key cells in the immune system that are designed to find and kill cells that are infected or defective.
Pathways:
$BPMC 3.37% core position
$MRTX 3.37% core position
$TPTX 3.37% core position
$SDGR 1.35%
$RVMD 2.7%
$RLAY 2.7%
$ERAS 0% considering but way too expensive
$RPTX 2.02%
$KNTE sold out as it was my weakest link
Protein Degraders:
$ARVN 1.35%
$KYMR 1.35% paying down a core position
$CCCC 2.02% paying down a core position
$GLUE 1.35% paying down a core position
CRISPR/Old Antibodies
$CRBU 1.35% paying down a core position
$BCAB 2.7% will sell out when I think its good opportunity.
CRISPR is way to crazy on values to waste money on here. It will implode someday, and I will be waiting.
1/ There are 2 types of protein degraders in development and a 3rd in concept phase of development. The first is the monoDAC, the second is the biDAC and the last is the triDAC.
2/ The monoDAC will bind with a covalent chemical bonding to the E3 ligase and alter its targeted function. It changes the shape of the E3 and directs it to place the ubiquitin molecule onto a protein it directs.
1/ The Proteasome is a cellular organelle. Its like the recycling bin for proteins. When a cell is done with a protein, it tags it for destruction in the process called ubiquitination.
2/ The proteasome will load these tagged proteins and break them down into peptides of about 7 to 10 amino acids in length for recycling. They will further be broken down after into single amino acids for reuse to build new proteins.
1/ Cells make, regulate and break down proteins constantly. They have a system to control the regulation of the proteins they produce. This is to remove unwanted proteins when no longer used.
2/ It also maintains healthy proteins as they degrade slowly over time. The process of ubiquitination is the tagging of these proteins by the cell for destruction. There are 3 enzymes that work in the process of ubiquitination.