Epigenetics and Disease PDF

In this section, we're going to talk about epigenetics and disease. Now, once again, this is module two, which covers in Chapter three, the four or five and six, this is McCance, Chapter six. Epigenetics is modifications that are not included in nucleotide sequence, but are nevertheless transmitted...

In this section, we're going to talk about epigenetics and disease. Now, once again, this is module two, which covers in Chapter three, the four or five and six, this is McCance, Chapter six. Epigenetics is modifications that are not included in nucleotide sequence, but are nevertheless transmitted when a somatic cell divides, when gametes are produced or both processed and modulate, modulate how a given set of genomic information gives rise to phenotype. So it's key. It's gene information and phenotype. Three key things. We're going to talk about DNA methylation, histone post translation modifications and RNA based mechanisms. DNA methylation plays a prominent role in human health and disease in females. The inactive X chromosome contains large amounts of methylation. The active X chromosomes are largely devoid of DNA methylation. So its key is showing some key that where there's large amounts of metals methylation, it's inactive. DNA with dense methylation are not actively transcribed. Epigenetic and activation of one of the two X chromosomes occurs during gastrulation, which is a phase of early embryonic development. The determination of which chromosome to be silenced, either the copy from the father or from the mother occurs at random and independently in each cell. Somatic masochism is the difference between the illegals active in two cells can confer two very different traits due to the random inactivation. It can arise for any X encoded trait females who inherit one normally and one disease also an X encoded gene then to have less severe disease phenotypes and males whose loan X chromosome bears a disease Lou. For example, there's a lower severity of colorblindness in females, histone modifications, so histones are positively charged. Proteins around which negatively charged DNA molecules are wound, facilitates compaction of DNA into the cellular nuclei, where all the DNA that comprises the human genome is found around the histones. It is only one of 40000 as well. Hetero chromatic is when a given segment of DNA is bound tightly to its histones. Eukaryotic is when a segment of DNA is only loosely bound to its histones. When it's loosely bound, transcription factors are able to access it and use it as a template for messenger RNA. The states of the individual segments of the genome play a critical role in determining the development potential of a given cell. So we'll continue talking about histone modification, histone acetylation, which tends to diminish the positive charge of histones, reduces the binding street to the DNA, histone methylation can either increase or decrease the bonding between DNA and histones, depending on the specific part of the histones, are added to mutations in genes that code histone modifying proteins have been implicated in various pathological states, including congenital heart disease. Histone modification is critical to normal development. Protamine evolution evolved evolutionarily derived from histones. They enable sperm DNA to achieve compaction even greater than histone bound DNA, improves hydrogenate dynamic features and facilitates movement changes in expression. Apartments have been found to be associated with infertility in males. And I'm going to going to attach an article about that. Epigenetics and human development totipotent. Each cell in the early embryo has the potential to give rise to any somatic cell. All the cells in a given individual contained almost exactly the same genetic information. It is the epigenetic information eventually placed on top of these sequences and enables them to achieve the diverse functions of different things. So that excels housekeeping genes, small percentage of genes that are necessary for function and maintenance of each. So they escape epigenetic silencing and remain transcriptional active and all or nearly all cells. Genomic imprinting violated both the maternal and paternal inherited copies contribute to Offspring phenotype model Lilit, the maternal copy is randomly chosen for inactivation and some somatic cells in the world, and then in others. The paternal copy is randomly chosen for inactivation imprinting, which is only about one percent. Other 99 percent being Balearic of monolithic. Either the maternal copy or the paternal copy is inherited. It's an either. Why is that? So then we have the genetic conflict hypothesis, which is only the hypothesis that remained true and research. Although both mother and father benefit genetically from the birth and survival of offspring, their interests are not entirely aligned. Since mothers make a large physiologic investment in each child, it's in their best interest to limit resources given to any one offspring and maintain capacity of their subsequent children. Except except in cases of lifelong monogamy, it's in the best interest of fathers for their child to exact maximum resources from its mother, and then limit the mother's ability to bear the additional offspring in the future. Imprinting genes from the mother are predicted to limit offspring size, whereas imprinting genes from the father are predicted to result in larger offspring. One important hallmark of imprinting associated diseases is the phenotype is critically dependent on whether the mutation is inherited from the mother or the father. Prader-Willi and Angelman Syndrome are two well known diseases of imprinting, and they're associated with deletion of about four million base pairs on the long arm of the chromosome 15. Prader-Willi syndrome occurs when this deletion is inherited from the father. It results in short stature. Aquitania small hands and feet, obesity, mild to moderate intellectual disability and hypogonadism. Angelman Syndrome is caused by the same deletion on the same chromosome, but it's inherited from the mother. Severe intellectual disability seizures and attacks iGate. Beckwith's Wagman syndrome is another well known imprinting disease, it's identifiable at birth because of the large size or gestational age, neonatal hypoglycemia, a large stone creases on the earlobe and also you have increased risk of developing Wilms tumor or a blastoma 20 30 percent of the cases are caused by inheritance of two copies of chromosome 11 from the father and no copy from the mother. This is called parental. That's only in contrast to the Prater, Willy and Angelman Syndrome. And it's caused in part by overexpression of a gene product sort of under expression Russel's severe syndrome that results in growth retardation, proportionately short stature, likely discrepancy and a small triangular shaped face. One third of the cases are caused by imprinting abnormalities of chromosome 11 15 that five of the 10 percent are caused by maternal parent or that something epigenetics and cognitive development and mental health that in utero ethanol exposure. So neural stem cells exposed to ethanol impair impairs their ability to differentiate to functional neurons. This correlates with this dense medicalisation. At Luchi, they're active in normal neuronal tissue, mental help, children who grow up in poverty, typical and atypical methylation and a serotonin receptor. PTSD causes alterations in gene expression and key neuronal pathways that are associated with atypical methylation in a large set of genes. Autism spectrum disorder is associated with altered DNA methylation at some boakai at the genetics and nutrition. During the winter of nineteen forty three, people in urban areas of the Netherlands suffered starvation as a result of Nazi blockage of food shipments. Individuals in utero during this time are more likely to suffer from obesity and diabetes as adults. The offspring of those children were found to be significantly smaller than children not affected by the blockade. So this is something that was genetically passed to the children. Epigenetics and aging monozygotic twins exhibit differences in methylation patterns of the DNA sequences of their somatic cells that often result in an increase in numbers of phenotypically differences. Twins with significant lifestyle differences tend to accumulate larger numbers of differences in methylation patterns. So as they age the twins, as they kind of diverged from each other and do different things, they get different methylation patterns on their DNA and significant lifestyle differences made that even greater. One of them was smoking versus non non smoking. Twin might have exhibited increases in the genome wide abundance of hydroxy methyl cysteine. So it was seen with time that many have proposed that senescence itself can be characterized as an epigenome phenomenon. As interesting study, metformin is effective in slowing senescence in the East. Studies have suggested that long term use of metformin may extend lifespan beyond non diabetic individuals. I would suggest there's something else happening with metformin, which in studies may modulate epigenetic path, epigenetic pathways with possible opportunities for lifespan, extension, epigenetics and cancer. Tumor cells often exhibit decreased methylation genome wide relative to normal cells of the same type, which can increase. That can increase. The activity of oncogene screening for epigenetic regulation has shown promise as a tool for detecting and characterizing cancer of the colon, breast and prostate. Other genetic based screening approaches have shown promise for bladder, lung and prostate cancer. Treatment of epigenetic disease, epigenetic modifications are potentially reversible. DNA can be methylated, histones can be modified to change the transcriptional state of nearby DNA and micro RNA encoding. Lokar can be up or down regulated DNA reflating agents. So this drug, five citizen known, has been used as a therapeutic drug in the treatment of leukemia. And Miloje dysplastic syndrome, histone diacetyl inhibitors, histone desales increases chromatin compaction causing decreased transcriptional activity treatment with HDFC inhibitors has shown promise in reducing cell division rates of breast, prostate and pancreas cancers. Micro RNA has shown promise for developing drugs that modify only the genes responsible for a specific cancer.